Antineoplastons: Adverse Effects

National Cancer Institute (NCI) at the National Institutes of Health (NIH)
Antineoplastons
Adverse Effects:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page6
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http://www.burzynskiclinic.com/scientific-publications.html
Interim Reports on Clinial Trials:

1. 10/2003

NEURO-ONCOLOGY

Burzynski, S.R., Weaver, R.A., Bestak, M., Lewy, R.I., Janicki, T.J., Jurida, G.F., Paszkowiak, J.K., Szymkowski, B.G., Khan, M.I.

Phase II study of Antineoplastons A10 and AS2-1 (ANP) in children with recurrent and progressive MULTICENTRIC GLIOMA

A preliminary report
http://www.burzynskiclinic.com/images/stories/Publications/970.pdf
Neuro-Oncology. 2003; 5: 358
Volume 5 Issue 4 October 2003

12 patients

10 evaluable

1 – serious (grade 3) toxicity: reversible tinnitus
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Interim Reports on Clinial Trials:

16. 2003

DRUGS IN R&D
Drugs in R and D
(Drugs in Research and Development)

BT-11

BRAIN STEM GLIOMA

Phase II study of antineoplaston A10 and AS2-1 in patients with recurrent diffuse intrinsic BRAIN STEM GLIOMA:

a preliminary report.
http://www.ncbi.nlm.nih.gov/pubmed/12718563
Burzynski, S.R., Lewy, R.I., Weaver, R.A., Axler, M.L., Janicki, T.J., Jurida, G.F., Paszkowiak, J.K., Szymkowski, B.G., Khan, M.I., Bestak, M.
http://www.ncbi.nlm.nih.gov/m/pubmed/12718563
Drugs R D. 2003;4(2):91-101
Drugs in R&D 2003;4:91-101
http://www.burzynskiclinic.com/images/stories/Publications/960.pdf
12 patients

10 evaluable

Pg. 96

Only mild and moderate toxicities were observed, which included:
3 – skin allergy
2 – anaemia
2 – fever
2 – hypernatraemia
1 – agranulocytosis
1 – hypoglycaemia
1 – myalgia
1 – numbness
1 – tiredness
1 – vomiting
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Review Articles on Clinical Trials:

1. 3/2004

INTEGRATIVE CANCER THERAPIES

Burzynski, S.R.

The Present State of Antineoplaston Research
http://www.burzynskiclinic.com/images/stories/Publications/994.pdf
Integrative Cancer Therapies 2004;3:47-58
Volume 3, No. 1, March 2004
DOI: 10.1177/1534735-403261964

Pg. 56

Adverse Reactions

Serious adverse reactions:
1.4% – anemia
0.5% – hypernatremia and fever

Moderate adverse reactions:
0.76% – skin rash
0.9% – slurred speech

Most patients experience increased diuresis, which may lead to dehydration and thirst

Adverse reactions observed have usually been transient and mild

Noted in our studies and due to phenylacetate, which is the main ingredient of AS2-1:
confusion
Reversible grade 1 somnolence

It’s suspected other adverse reactions observed in our studies were due to A10.

They weren’t observed by Buckner et al since they used approximately 50 times lower dosages of A10 in their study.

On the other hand, A10 induces diuresis, which may result in rapid elimination of AS2-1 through kidneys, which will lower concentration of AS2-1 in plasma and reduce chances for higher grade toxicity observed by Buckner et al. [49]

49. Burzynski SR. Efficacy of antineoplastons A10 and AS2-1.
http://www.ncbi.nlm.nih.gov/pubmed/10377942/
Mayo Clin Proc. 1999;74:641-642.
http://www.ncbi.nlm.nih.gov/m/pubmed/10377942/
Mayo Clin Proc. 1999 Jun;74(6):641-2.
http://www.sciencedirect.com/science/article/pii/S0025619611641438
Mayo Clinic Proceedings
Volume 74, Issue 6 , Page 641, June 1999

Buckner et al described:
reversible grade 2 or 3 neurological toxicity, consisting of:
confusion
exacerbation of an underlying seizure disorder
transient somnolence
[48]

48. Buckner JD, Malkin MG, Reed E, et al. Phase II study of antineoplaston A10 (NSC 648539) and AS2-1 (NSC 620061) in patients with recurrent glioma. Mayo Clin Proc. 1999;74:137-145.
http://www.ncbi.nlm.nih.gov/pubmed/10069350/
Mayo Clin Proc. 1999 Feb;74(2):137-45.
http://www.ncbi.nlm.nih.gov/m/pubmed/10069350/
Mayo Clinic Proceedings
Volume 74, Issue 2, February 1999, Pages 137–145
http://www.sciencedirect.com/science/article/pii/S0025619611638354
Department of Oncology, Mayo Clinic Rochester, Minnesota, USA.
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Case Reports:

4. 9/2004

INTEGRATIVE CANCER THERAPIES

Special exception (SE) to BT-11

BRAIN STEM GLIOMA

Burzynski, S.R., Lewy, R.I., Weaver, R., Janicki, T., Jurida, G., Khan, M., Larisma, C.B., Paszkowiak, J., Szymkowski, B.

Long-term survival and complete response of a patient with recurrent diffuse intrinsic brain stem GLIOBLASTOMA MULTIFORME
http://www.burzynskiclinic.com/images/stories/Publications/1145.pdf
Integrative Cancer Therapies 2004;3:257-261
Volume 3, Number 3 September 2004
DOI: 10.1177/1534735404267748

Pg. 257

40 – age

Mild reversible side effects

Pg. 258

9/30/2009 – admitted for administration of treatment
Mild hypernatremia – On several occasions discontinued treatment from 1 to 3 days
Increased fatigue – off treatment 2 days
3/29/2000 – White blood cell (WBC) count decreased and discontinued treatment for 3 days

Pg. 259

7/10/2000 – White blood cell (WBC) count decreased and discontinued treatment until treatment restarted 7/13/2000
7/15/2000 – discontinued treatment elevation of transaminases (serum glutamic oxaloacetic transaminase; serum glutamic pyruvic transaminase) until restarted 7/28/2000
8/2001 – developed persistent diarrhea and was referred to a gastroenterologist, but there were no pathological findings except for changes related to obesity
8/21/2001 treatment discontinued due to resolution of tumor
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Interim Reports on Clinial Trials:

2. 10/2004

NEURO-ONCOLOGY

BT-20

Patients With GLIOBLASTOMA MULTIFORME (GBM)

Weaver, R.A., Burzynski, S.R., Bestak, M., Lewy, R.I., Janicki, T.J., Szymkowski, B., Jurida, G., Khan, M.I., Dolgopolov, V.

Phase II study of Antineoplastons A10 and AS2-1 (ANP) in recurrent GLIOBLASTOMA MULTIFORME
http://www.burzynskiclinic.com/images/stories/Publications/1218.pdf
Neuro-Oncology. 2004; 6: 384
Volume 6 Issue 4 October 2004
Abstracts from the Society for Neuro-Oncology Ninth Annual Meeting, Toronto, Ontario, Canada, November 18-21, 2004

22 evaluable patients
(6 men / 16 women / 27-63 /47 – median age)

Pg. 385

2 – grade toxicity: hypernatremia
2 – grade toxicity: somnolence
1 – grade 3 toxicity: anemia
1 – fatigue
1 – fever
1 – headache
1 – nausea
1 – tinnitus
1 – vomiting
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Interim Reports on Clinial Trials:

3. 10/2004 (DBSG)

NEURO-ONCOLOGY

Burzynski, S.R., Weaver, R. Bestak. M., Lewy, R.I., Janicki, T., Jurida, G., Szymkowski, B., Khan, M., Dolgopolov, V.

Long-term survivals in phase II studies of Antineoplastons A10 and AS2-1 (ANP) in patients with diffuse intrinsic BRAIN STEM GLIOMA
http://www.burzynskiclinic.com/images/stories/Publications/1219.pdf
Neuro-Oncology. 2004; 6: 386
Volume 6 Issue 4 October 2004

60 patients
(31 treated under Special Exception)

1 – reversible grade 3 toxicity: anemia
1 – reversible grade 3 toxicity: hypertension
1 – reversible grade 3 toxicity: hypokalemia
1 – reversible grade 3 toxicity: neutropenia
1 – reversible grade 3 toxicity: allergic skin rash
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Interim Reports on Clinial Trials:

4. 10/2004 (AT/RT of CNS)

NEURO-ONCOLOGY

Burzynski, S.R., Weaver, R. Bestak. M., Janicki, T., Jurida, G., Szymkowski, B., Khan, M., Dolgopolov, V.

Phase II studies of antineoplastons A10 and AS2-1 (ANP) in children with atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system

A preliminary report
http://www.burzynskiclinic.com/images/stories/Publications/1146.pdf
Neuro-Oncology. 2004; 6: 427
Volume 6 Issue 4 October 2004
Abstracts from the Eleventh International Symposium on Pediatric Neuro-Oncology, Boston, Massachusetts, June 13-16, 2004

11 children patients
(7 treated under Special Exception)

8 evaluable

1 – serious toxicity: reversible hypernatremia
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Interim Reports on Clinial Trials:

5. 10/2004

NEURO-ONCOLOGY

BT-12

CHILDREN WITH PRIMITIVE NEUROECTODERMAL TUMORS (PNET)

Burzynski, S.R., Weaver, R. Bestak. M., Janicki, T., Szymkowski, B., Jurida, G., Khan, M., Dolgopolov, V.

Treatment of PRIMITIVE NEUROECTODERMAL TUMORS (PNET) with antineoplastons A10 and AS2-1 (ANP)

Preliminary results of phase II studies
http://www.burzynskiclinic.com/images/stories/Publications/1147.pdf
Neuro-Oncology. 2004; 6: 428
Volume 6 Issue 4 October 2004
Abstracts from the Eleventh International Symposium on Pediatric Neuro-Oncology

17 patients
(12 months – 23 / 6 – median age)

15 evaluable

1 – serious side effect: anemia
1 – serious side effect: fever
1 – serious side effect: granulocytopenia
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Interim Reports on Clinial Trials:

18. 6/2005

INTEGRATIVE CANCER THERAPIES

BT-12

CHILDREN WITH PRIMITIVE NEUROECTODERMAL TUMORS (PNET)

CAN-01

CAN-1

PATIENTS WITH REFRACTORY MALIGNANCIES

Burzynski, S.R., Weaver, R.A., Janicki, T., Szymkowski, B., Jurida, G., Khan, M., Dolgopolov, V.

Long-term survival of high-risk pediatric patients with PRIMITIVE NEUROECTODERMALTUMORS treated with Antineoplastons A10 and AS2-1
http://www.ncbi.nlm.nih.gov/pubmed/15911929
Integrative Cancer Therapies 2005;4(2):168-177
http://www.ncbi.nlm.nih.gov/m/pubmed/15911929
Integr Cancer Ther. 2005 Jun;4(2):168-77
http://www.burzynskiclinic.com/images/stories/Publications/1220.pdf
DOI: 10.1177/1534735405276835
http://m.ict.sagepub.com/content/4/2/168.long?view=long&pmid=15911929
Pg. 168

13 children patients – recurrent disease or high risk

10 males / 3 females

(1 – 11 – age / 5 years, 7 months – median age)

3 – younger than 3

Pgs. 168 and 170

8 – Medulloblastoma
3 – pineoblastoma
2 – other PRIMITIVE NEUROECTODERMALTUMORS (PNET)

Pg. 168

10-BT-12 (7 males / 3 females)

3 – CAN-01 (3 males)

Pgs. 168 and 173

serious side effects:
1 – anemia
1 – fever
1 – granulocytopenia
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Interim Reports on Clinial Trials:

BT-11

BRAIN STEM GLIOMA

7. 7/2005

Burzynski, S.R., Weaver, R.A., Janicki, T.J., Burzynski, B., Jurida, G. Targeted therapy with ANP in children less than 4 years old with inoperable BRAIN STEM GLIOMAs. Neuro-Oncology. 2005; 7:300.
http://www.burzynskiclinic.com/images/stories/Publications/1224.pdf
Volume 7 Issue 3 July 2005
Abstracts from the World Federation of Neuro-Oncology Meeting

2 trials

Intrinsic diffuse brain stem glioma (BSG)

10 assessable patients

Less than 4 years old
(3 months – 3 years)

7 – no biopsy: dangerous tumor location
2 – anaplastic astrocytoma
1 – pilocytic astrocytoma

Serious toxicities:
Reversible anemia
Hypokalemia

No chronic toxicities
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Interim Reports on Clinial Trials:

BT-03


BT-11

BRAIN STEM GLIOMA (BSG)

BT-18

6. MIXED GLIOMA

ADULT PATIENTS WITH MIXED GLIOMA

“mixed glioma”, a type of PMBT

CAN-01

CAN-1

PATIENTS WITH REFRACTORY MALIGNANCIES

19. 3/2006

Burzynski, S.R., Janicki, T.J., Weaver, R.A., Burzynski, B. Targeted therapy with Antineoplastons A10 and AS2-1 of high grade, recurrent, and progressive BRAINSTEM GLIOMA. Integrative Cancer Therapies 2006;5(1):40-47
http://www.ncbi.nlm.nih.gov/pubmed/16484713
Integr Cancer Ther. 2006 Mar;5(1):40-7
http://www.ncbi.nlm.nih.gov/m/pubmed/16484713
DOI: 10.1177/1534735405285380
http://www.burzynskiclinic.com/images/stories/Publications/5825.pdf

http://m.ict.sagepub.com/content/5/1/40.long?view=long&pmid=16484713
Pg. 40

4 phase 2 trials

BRAINSTEM GLIOMA (BSG)

patients with inoperable tumor of high-grade pathology (HBSG)
glioblastoma

recurrent diffuse intrinsic glioblastomas and ANAPLASTIC ASTROCYTOMAs of brainstem

Pgs. 40 – 41 and 42

4 – glioblastomas (gliobastoma multiforme (GBM)) (GBM / BSG)

14 – anaplastic HBSG (patients with inoperable tumor of high-grade pathology (HBSG)) (Anaplastic astrocytoma / Anaplastic astrocytoma/mixed glioma)

14 – diffuse intrinsic tumors

12 – recurrence

18 patients

Pg. 42

(8 males / 10 females)

2 – 42 – age (10 – median age)

Pg. 43

BT-03 – 1 / female
BT-11 – 13 (8 males/5 females)
BT-18 – 1 / female
BT-22 – 2 / females
CAN-01 – 1 / female

Pg. 44

High-grade, recurrent, and progressive brainstem gliomas

Pgs. 40 and 45

Antineoplastons tolerated very well
1 – grade 4 toxicity (reversible anemia)

Pg. 45

2 – grade 3 toxicities: reversible anemia

Generally, the treatment was well tolerated and was free from chronic toxicities
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Interim Reports on Clinial Trials:

BT-11

BRAIN STEM GLIOMA

8. 10/2006

Burzynski, S.R., Janicki, T.J., Weaver, R.A., Szymkowski, B.G., Khan, M.I., Dolgopolov, V. Treatment of multicentric BRAINSTEM GLIOMAs with antineoplastons (ANP) A10 and AS2-1. Neuro-Oncology. 2006; 8:466.
http://www.burzynskiclinic.com/images/stories/Publications/2105.pdf
Volume 8 Issue 4 October 2006
Abstracts for the Eleventh Annual Meeting of the Society for Neuro-Oncology (SNO)

Brainstem gliomas and multicentric tumors (MBSG)

19 evaluable patients

3.9 – 40.8 (9.2 – median age)

(90% less than 18 years old)

95% diffuse intrinsic brain stem glioma
5% cervicomedullary tumor

The patients didn’t experience any serious toxicities (grades III – IV), and there were no chronic toxicities
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Interim Reports on Clinial Trials:

BT-11

BRAIN STEM GLIOMA

9. 4/2007 (NDBSG)

Burzynski, S.R., Weaver, R.A., Janicki, T.J., Jurida, G.F., Szymkowski, B.G., Kubove, E. Phase II studies of Antineoplastons A10 and AS 2-1 (ANP) in children with newly diagnosed diffuse, intrinsic BRAINSTEM GLIOMAs. Neuro-Oncology 2007; 9:206.
http://www.burzynskiclinic.com/images/stories/Publications/4021.pdf
Volume 9 Issue 2 April 2007
Abstracts from the Twelfth International Symposium on Pediatric Neuro-Oncology

20 assessable children

3 months – 20 – age

5 – high-grade gliomas

Serious toxicities included:
5 – anemia
1 – elevation of transaminases
1 – hypokalemia
1 – skin rash
There were no chronic toxicities
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Interim Reports on Clinical Trials:

10. 6/2008 (OPG)

BT-23 – CHILDREN WITH VISUAL PATHWAY GLIOMA

Phase II study of antineoplastons A10 and AS2-1 (ANP) in CHILDREN WITH optic PATHWAY GLIOMA:

A preliminary report
http://www.burzynskiclinic.com/images/stories/Publications/7287.pdf
Neuro-Oncology 2008; 10:450
Volume 10 Issue 3 June 2008

Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Samuel, Shiney
Szymkowski, Barbara G.
Walczak, Marek
Weaver, Robert A.

16.5 months (1 year 4.5 months) – Median antineoplaston treatment

6/2008 – Protocol – CHILDREN WITH optic PATHWAY GLIOMA

12 Evaluable Children Patients
(7 months – 16 years / 6 years 3 months – Median age)
——————————————————————
0 – lost to follow-up
——————————————————————
No grade 3 or 4 toxicities
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Interim Reports on Clinical Trials:

11. 10/2008

(BT-8 – PATIENTS WITH ANAPLASTIC ASTROCYTOMA
9)

(BT-15 – ADULT PATIENTS WITH ANAPLASTIC ASTROCYTOMA
17)

Phase II study of antineoplastons A10 and AS2-1 (ANP) in PATIENTS WITH newly diagnosed ANAPLASTIC ASTROCYTOMA:

A preliminary report
http://www.burzynskiclinic.com/images/stories/Publications/7853.pdf
Volume 10 Issue 5 October 2008
Neuro-Oncology 2008; 10:821
Abstracts for the Thirteenth Annual Meeting of the Society for Neuro-Oncology, November 20-23, 2008

Burzynski, Gregory
Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Samuel, Shiney
Szymkowski, Barbara G.
Weaver, Robert A.

FDA monitored study

5.7 months – Median Duration of Treatment

10/2008 – Protocol – Patients with Newly Diagnosed ANAPLASTIC ASTROCYTOMA (AA)

20 Evaluable Patients
(22 – 64 years / 40 – Median age)
——————————————————————
2 / 10% – grade 3 toxicity possibly related to antineoplastons (ANP)
(Shortness of breath / generalized weakness)

Interim Reports on Clinical Trials:

12. 12/2008

(BT-8 – PATIENTS WITH ANAPLASTIC ASTROCYTOMA: 9)

(BT-15 – ADULT PATIENTS WITH ANAPLASTIC ASTROCYTOMA: 17)

Phase II study of antineoplastons A10 and AS2-1 infusions (ANP) in PATIENTS WITH recurrent ANAPLASTIC ASTROCYTOMA
http://www.burzynskiclinic.com/images/stories/Publications/7898.pdf
Neuro-Oncology 2008; 10:1067
Volume 10 Issue 6 December 2008
Abstracts for the Eighth Congress of the European Association for Neuro-Oncology (EANO), Sept. 12-14, 2008, Barcelona, Spain

Burzynski, Gregory
Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Szymkowski, Barbara G.
Walczak, Marek
Weaver, Robert A.

6.5 months – Median duration of treatment

FDA-monitored phase II clinical trial

12/2008 – Protocol – ADULTS WITH recurrent ANAPLASTIC ASTROCYTOMA (AA)

20 – Evaluable Assessable Adult Patients
(20 – 51 years / 41 – Median age)
——————————————————————
1 / 5% – serious toxicity of hypernatremia
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Case Reports:

BT-11 special exception (SE)

BRAIN STEM GLIOMA

1. 12/2009

Weaver, R.A., Szymkowski, B., Burzynski, S.R. Over a 10-year survival and complete response of a patient with diffuse intrinsic BRAINSTEM GLIOMA (DBSG) treated with antineoplastons (ANP). Neuro-Oncology 2009; 11:923.
http://www.burzynskiclinic.com/images/stories/Publications/8638.pdf
Volume 11 Issue 6 December 2009
Abstracts from the Third Quadrennial Meeting of the World Federation of Neuro-Oncology (WFNO) and the Sixth Meeting of the Asian Society for Neuro-Oncology (ASNO)
May 11-14, 2009
Yokohama, Japan

10.5 – age / female

1 episode of grade 3 vomiting which resolved within 3 days
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Interim Reports on Clinial Trials:

BT-11

BRAIN STEM GLIOMA

13. 12/2009 (DBSG)

Burzynski, S.R., Janicki, T.J., Weaver, R.A., Szymkowski, B., Burzynski, G.S. Phase II study of antineoplastons A10 and AS2-1 in patients with BRAINSTEM GLIOMA. Protocol BC-BT-11. Neuro-Oncology 2009, 11:951.
http://www.burzynskiclinic.com/images/stories/Publications/8639.pdf
Volume 11 Issue 6 December 2009
Abstracts from the Third Quadrennial Meeting of the World Federation of Neuro-Oncology (WFNO) and the Sixth Meeting of the Asian Society for Neuro-Oncology (ASNO)
May 11-14, 2009
Yokohama, Japan

40 patients

12 not evaluable

28 evaluable (ST) (23 children / 5 young adults)

12 – newly diagnosed / 16 previously treated)

Additional 52 evaluable (40 children / 12 young adults) treated under special exception (SE) (18 newly diagnosed)

ANP was well tolerated with serious toxicities occurring in less than 10% of patients in both groups:
anemia
dyspnea
elevated transaminases
fatigue
hypernatremia
hypokalemia
polyuria
skin rash
somnolence
subcutaneous extravasation
vomiting

No chronic toxicities
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Interim Reports on Clinical Trials:

14. 6/2010

BT-13 – CHILDREN WITH LOW GRADE ASTROCYTOMA

A Phase II Study of Antineoplaston A-10 and AS-1 Injections in CHILDREN WITH LOW-GRADE ASTROCYTOMAs.
http://www.burzynskiclinic.com/images/stories/Publications/8397.pdf
Neuro-Oncology 2010; 12, ii95.
Volume 12 Issue 6 June 2010

Acelar, Sheryll S.
Burzynski, Gregory S.
Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Szymkowski, Barbara G.
Weaver, Robert A

17 / 100% – Evaluable for Safety

12 or more weeks or at least 4 weeks of Antineoplastons (ANP) but developed Progressive Disease (PD)
Patients Evaluable for Efficacy

83 weeks – Median Antineoplastons (ANP) (15 / 100% – Evaluable Patients)

6/2010 – Protocol – CHILDREN WITH Recurrent and / or Progressive LOW-GRADE ASTROCYTOMA (LGA)

17 Patients Accrued
(20 months {1 year 8 months} – 210 months {17 years 6 months} / 129 months {10 years 9 months} – Median age)
15 Evaluable Patients

Patients Showing Stable Disease (47 – 85 days / 60 – Median days of Antineoplastons (ANP))
Patients Showing Progressive Disease (47 – 85 days / 60 – Median days of Antineoplastons (ANP))
——————————————————————
Minimal toxicity
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Interim Reports on Clinical Trials:

15. 11/2010

BT-18 – ADULT PATIENTS WITH MIXED GLIOMA

Preliminary Results of a Phase II Study of Antineoplastons A10 and AS2-1 (ANP) in Adult Patients with Recurrent Mixed Gliomas.
http://www.burzynskiclinic.com/images/stories/Publications/8637.pdf
Neuro-Oncology 2010; 12:iv72.
Volume 12 Supplement 4 November 2010

Acelar, Sheryll S.
Burzynski, Gregory S.
Burzynski, Stanislaw Rajmund
Janicki, Tomasz J.
Szymkowski, Barbara G.
Weaver, Robert A

7 / 35% – not evaluated due to inadequate duration of treatment and lack of follow-up Magnetic Resonance Imaging (MRI) scans

4.4 months – median duration of treatment

11/2010 – Protocol – Adult Patients with Recurrent Mixed Gliomas

20 – Children Patients Accrued
13 – Evaluable Patients
(9 men / 4 women: 29 – 54 years / 38 – Median age)
——————————————————————
Antineoplastons (ANP) was well tolerated with the most common side effects being:
Dysgeusia
Hypernatremia
Hypersensitivity
Myalgias
Nausea
Urinary frequency

1 – Serious (grade 3) toxicity (urinary frequency)

No grade 4 toxicities

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Phenylbutyrate (PB)

Dvorit D. SAMID learned about PHENYLBUTYRATE (PB) from Burzynski
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Antineoplastons AS2-1 and AS2-5 are DERIVED FROM A10
� � � � � � � � � � � � � � � � �
Phenylacetylglutaminate (PAG or PG) and Phenylacetate (PN) are metabolites of PHENYLBUTYRATE (PB) and are constituents of antineoplaston AS2-1
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National Cancer Institute (NCI)
at the National Institutes of Health (NIH) Antineoplastons
General Information:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page2
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Sodium PHENYLBUTYRATE (PB)
Year – Pubmed (110 entries)
1958 1st entry
1995 1st clinical trial
2001 Phase 1
2009 Phase 2
2012 Phase 3
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PHENYLBUTYRATE (PB)
19 (PHENYLBUTYRATE (PB + SAMID)
http://www.ncbi.nlm.nih.gov/m/pubmed/?term=Phenylbutyrate+Samid
� � � � � � � � � � � � � � � � �
IV. Aetna considers SODIUM PHENYLBUTYRATE medically necessary for the treatment of acute promyelocytic leukemia and malignant glioma
http://www.aetna.com/cpb/medical/data/200_299/0240.html
� � � � � � � � � � � � � � � � �
The FDA has approved SODIUM PHENYLBUTYRATE as a treatment to remove ammonia from the bloodstream in individuals with urea cycle disorders
� � � � � � � � � � � � � � � � �
SODIUM PHENYLBUTYRATE was given an orphan drug designation by the FDA for use as an adjunct to surgery, radiation therapy, and chemotherapy for treatment of individuals with primary or recurrent malignant glioma
http://www.anthem.com/medicalpolicies/policies/mp_pw_a050524.htm
� � � � � � � � � � � � � � � � �
Cumulative List of all Products that have received Orphan Designation: Total active designations: 2002 Effecive: (sic – Effective) 5/5/2009
http://www.fda.gov/downloads/forindustry/developingproductsforrarediseasesconditions/howtoapplyfororphanproductdesignation/ucm162066.xls
PHENYLBUTYRATE (PB) and SODIUM PHENYLBUTYRATE are listed alphabetically in the lower 1/4th of this document
� � � � � � � � � � � � � � � � �
Pubmed 110 entries
Sodium PHENYLBUTYRATE
“Sodium PHENYLBUTYRATE (aka PB) …”
� � � � � � � � � � � � � � � � �
If they’re going to include it in a phase 3 study, than it’s “fair game”
http://www.ncbi.nlm.nih.gov/m/pubmed/22961727
Hepatology
Early View (Online Version of Record published before inclusion in an issue)

Article first published online: 3 JAN 2013

DOI: 10.1002/hep.26058
http://onlinelibrary.wiley.com/doi/10.1002/hep.26058/abstract;jsessionid=34AE3D61DEEF5356F147DE74B26759F9.d01t03
Article:
http://onlinelibrary.wiley.com/doi/10.1002/hep.26058/full
References:
http://onlinelibrary.wiley.com/doi/10.1002/hep.26058/references
Cited by:
http://onlinelibrary.wiley.com/doi/10.1002/hep.26058/citedby

Hepatology. 2012 Sep 7. doi: 10.1002/hep.26058. [Epub ahead of print]
� � � � � � � � � � � � � � � � �
1990 – Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1.
http://www.ncbi.nlm.nih.gov/m/pubmed/2152694/
BURZYNSKI, S. R., Kubove E., Burzynski, B.
Drugs Exp. Clin. Res., 16: 361-369, 1990.
� � � � � � � � � � � � � � � � �
1991 – Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC288233/
SAMID D., Shack S., Myers C.
J. Clin. Investig., 91: 2288-2295, 1991.
J Clin Invest. 1993 May; 91(5): 2288–2295.
doi: 10.1172/JCI116457
PMCID: PMC288233

References:

SAMID D, Flessate DM, Friedman RM. Interferon-induced revertants of ras-transformed cells:

resistance to transformation by specific oncogenes and retransformation by 5-azacytidine. Mol Cell Biol. 1987 Jun;7(6):2196–2200.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC365343/

http://www.ncbi.nlm.nih.gov/m/pubmed/2439904/
SAMID D, Shack S, Sherman LT. Phenylacetate:

a novel nontoxic inducer of tumor cell differentiation. Cancer Res. 1992 Apr 1;52(7):1988–1992.
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/

http://cancerres.aacrjournals.org/content/52/7/1988
SAMID D, Yeh A, Prasanna P. Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. Blood. 1992 Sep 15;80(6):1576–1581.
http://www.ncbi.nlm.nih.gov/m/pubmed/1381630/
Dover GJ, Brusilow S, SAMID D. Increased fetal hemoglobin in patients receiving sodium 4-PHENYLBUTYRATE. N Engl J Med. 1992 Aug 20;327(8):569–570.
http://www.ncbi.nlm.nih.gov/m/pubmed/1378939/
� � � � � � � � � � � � � � � � �
4/1/1992Phenylacetate:

A novel non-toxic inducer of tumor cell differentiation
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/
SAMID D, Shack S , Sherman L T
http://cancerres.aacrjournals.org/content/52/7/1988
Cancer Res 52:1988,1992
Cancer Res. 1992 Apr 1;52(7):1988-92.
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, Maryland.
↵1 Supported by Elan Pharmaceutical Corporation Grant G174ED.
Reference: 12 (SAMID, D.)
� � � � � � � � � � � � � � � � �
8/20/1992 – Increased fetal hemoglobin in patients receiving sodium 4-PHENYLBUTYRATE.
http://www.ncbi.nlm.nih.gov/m/pubmed/1378939/
Dover GJ, Brusilow S, SAMID D
N Engl J Med 327569, 1992
N Engl J Med. 1992 Aug 20;327(8):569–570.
� � � � � � � � � � � � � � � � �
9/15/1992 – Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate.
http://www.ncbi.nlm.nih.gov/m/pubmed/1381630/
SAMID D, Yeh A, Prasanna P
Blood 80:1576, 1992
Blood. 1992 Sep 15;80(6):1576–1581.
Blood. 1992 Sep 15;80(6):1576-81.
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, MD.

References:

15. SAMID D, Shack S, Ti-Sherman L Phenylacetate-A novel nontoxic inducer of tumor cell differentiation. Cancer Res 52:1988, 1992
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/
Cancer Res. 1992 Apr 1;52(7):1988-92.
http://cancerres.aacrjournals.org/content/52/7/1988
20. SAMID D, Flessate DM, Friedman RM: Interferon-induced revertants of ras-transformed cells:

Resistance to transformation by specific oncogenes and retransformation by 5-azacytidine. Mol Cell Biol7:2196,1987
http://www.ncbi.nlm.nih.gov/m/pubmed/2439904/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC365343/
21. Rimoldi D, Srikantan V, Wilson VL, Bassin RH,SAMID D: Increased sensitivity of nontumorigenic fibroblasts expressing ras or myconcogenes to malignant transformation induced by 5-aza-2‘- deoxycytidine. Cancer Res 51:324,1991
http://www.ncbi.nlm.nih.gov/m/pubmed/1703037/

http://m.cancerres.aacrjournals.org/content/51/1/324.abstract

http://m.cancerres.aacrjournals.org/content/51/1/324.full.pdf

http://cancerres.aacrjournals.org/content/51/1/324
34. Dover GJ, Brusilow S, SAMID D: Increased fetal hemoglobin in patients receiving sodium 4-PHENYLBUTYRATE. N Engl J Med 327569,1992
N Engl J Med. 1992 Aug 20;327(8):569–570.
http://www.ncbi.nlm.nih.gov/m/pubmed/1378939/
� � � � � � � � � � � � � � � � �
5/1993 – Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic, pharmacological concentrations of phenylacetate.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC288233/
SAMID D, Shack S, Myers CE:
J Clin Invest 91:2288, 1993
J Clin Invest. 1993 May; 91(5): 2288–2295.
doi: 10.1172/JCI116457
PMCID: PMC288233

References:

9. SAMID D, Flessate DM, Friedman RM. Interferon-induced revertants of ras-transformed cells: resistance to transformation by specific oncogenes and retransformation by 5-azacytidine. Mol Cell Biol. 1987 Jun;7(6):2196–2200.
http://www.ncbi.nlm.nih.gov/m/pubmed/2439904/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC365343/

http://mcb.asm.org/content/7/6/2196.full.pdf
13. SAMID D, Shack S, Sherman LT. Phenylacetate:

a novel nontoxic inducer of tumor cell differentiation. Cancer Res. 1992 Apr 1;52(7):1988–1992.
Cancer Res 52:1988, 1992
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/
Cancer Res. 1992 Apr 1;52(7):1988-92.
http://cancerres.aacrjournals.org/content/52/7/1988
14. SAMID D, Yeh A, Prasanna P. Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. Blood. 1992 Sep 15;80(6):1576–1581.
Blood 80:1576, 1992
Blood. 1992 Sep 15;80(6):1576-81.
http://www.ncbi.nlm.nih.gov/m/pubmed/1381630/
17. Dover GJ, Brusilow S, SAMID D. Increased fetal hemoglobin in patients receiving sodium 4-PHENYLBUTYRATE. N Engl J Med. 1992 Aug 20;327(8):569–570.
N Engl J Med 327569,1992
http://www.ncbi.nlm.nih.gov/m/pubmed/1378939/
33. D. SAMID
� � � � � � � � � � � � � � � � �
10/1/1993 – Enhanced fetal
hemoglobin production by phenylacetate and 4-PHENYLBUTYRATE in erythroid precursors derived from normal blood donors and patients with sickle cell anemia and P-thalassemia
http://www.ncbi.nlm.nih.gov/m/pubmed/7691251/
Fibach E, Prasanna P, Rodgers GP, SAMID D:
Blood 822203, 1993
Blood. 1993 Oct 1;82(7):2203-9.
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.

References:

15. (SAMID D)

19. SAMID D, Yeh A, Prasanna P Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. Blood 80:1576, 1992
Blood. 1992 Sep 15;80(6):1576–1581.
http://www.ncbi.nlm.nih.gov/m/pubmed/1381630/
20. Dover GJ, Brusilow S, SAMID D: Increased fetal hemoglobin in patients receiving sodium 4-PHENYLBUTYRATE. N Engl J Med 327569, 1992
N Engl J Med. 1992 Aug 20;327(8):569–570.
http://www.ncbi.nlm.nih.gov/m/pubmed/1378939/
3I. SAMID D, Shack S, Ti-Sherman L Phenylacetate-A novel
nontoxic inducer of tumor cell differentiation. Cancer Res 52:1988, 1992
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/
Cancer Res. 1992 Apr 1;52(7):1988-92.
http://cancerres.aacrjournals.org/content/52/7/1988
32. SAMID D, Shack S, Myers CE: Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic, pharmacological concentrations of phenylacetate. J Clin Invest 91:2288, 1993
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC288233/
� � � � � � � � � � � � � � � � �
4/1/1994 Phase 1
http://www.ncbi.nlm.nih.gov/m/pubmed/8137283
A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer
http://m.cancerres.aacrjournals.org/content/54/7/1690.abstract
Thibault A, Cooper MR, Figg WD, Venzon DJ, Sartor AO, Tompkins AC, Weinberger MS, Headlee DJ, McCall NA, SAMID D, et al.
http://m.cancerres.aacrjournals.org/content/54/7/1690.full.pdf
Clinical Pharmacology Branch, National Cancer Institute, NIH, Bethesda, Maryland
Cancer Res. 1994 Apr 1;54(7):1690-4.
Cancer Res 54(7):1690-4 (1994), PMID.8137283
recent version of this article at: http://cancerres.aacrjournals.org/content/54/7/1690
References:

8. SAMID, A., Shack, S., and Sherman, L. T. Phenylacetate:

a novel nontoxic inducer of tumor cell differentiation. Cancer Res., 52: 1988-1992, 1992.
Cancer Res 52:1988, 1992
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/
Cancer Res. 1992 Apr 1;52(7):1988-92.
http://cancerres.aacrjournals.org/content/52/7/1988
9. SAMID, D., Yen, A., and Prasana, P. Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. Blood, 80: 1576-1581, 1992.
Blood 80:1576, 1992
Blood. 1992 Sep 15;80(6):1576–1581.
http://www.ncbi.nlm.nih.gov/m/pubmed/1381630/
10. SAMID, D., Shack, S., and Myers, C. E. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate. J. Clin. Invest., 91: 2288-2295, 1993.
J Clin Invest 91:2288, 1993
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC288233/
11. SAMID. D., Ram, Z., Hudgins, W. R., Shack, S., Liu, L., Walbridge, S., Oldfield, E. H., Myers, C. E. Selective activity of phenylacetate against malignant gliomas:

resemblance to fetal brain damage in phenylketonuria. Cancer Res., 54: 891-895, 1994.
http://www.ncbi.nlm.nih.gov/m/pubmed/8313377/
12. Dover, G. J., Brusilow, S., and SAMID, D. Increased fetal hemoglobin in patients receiving sodium 4-PHENYLBUTYRATE. N. Engl. J. Med., 327: 569-570, 1992.
N Engl J Med 327569, 1992
N Engl J Med. 1992 Aug 20;327(8):569–570.
http://www.ncbi.nlm.nih.gov/m/pubmed/1378939/
13. BURZYNSKI, S. R., Kubove E., Burzynski, B. Treatment of hormonally refractory cancer of the prostate with antineoplaston AS2-1. Drugs Exp. Clin. Res., 16: 361-369, 1990.
http://www.ncbi.nlm.nih.gov/m/pubmed/2152694/
� � � � � � � � � � � � � � � � �
1/1/1995 1st clinical trial
http://www.ncbi.nlm.nih.gov/m/pubmed/7528572
Oral sodium PHENYLBUTYRATE therapy in homozygous beta thalassemia:

a clinical trial
http://m.bloodjournal.hematologylibrary.org/content/85/1/43.full.pdf#page=1
Collins AF, Pearson HA, Giardina P, McDonagh KT, Brusilow SW, Dover GJ.
Blood. 1995 Jan 1;85(1):43-9.
Johns Hopkins University School of Medicine, Baltimore, MD.

References:

14. SAMID D, Shack S , Sherman L T

Phenylacetate:

A novel non-toxic inducer of tumor cell differentiation
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/
Cancer Res 52:1988,1992
Cancer Res. 1992 Apr 1;52(7):1988-92.
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, Maryland.
http://cancerres.aacrjournals.org/content/52/7/1988
16. Fibach E, Prasanna P, Rodgers GP, SAMID D:

Enhanced fetal
hemoglobin production by phenylacetate and 4-PHENYLBUTYRATE in erythroid precursors derived from normal blood donors and patients with sickle cell anemia and P-thalassemia
http://www.ncbi.nlm.nih.gov/m/pubmed/7691251/
Blood 822203, 1993
Blood. 1993 Oct 1;82(7):2203-9.
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel.

28. Dover GJ, Brusilow SW, SAMID D:

Increased fetal hemoglobin in patients receiving sodium 4-PHENYLBUTYRATE
http://www.ncbi.nlm.nih.gov/m/pubmed/1378939/
N Engl JMed 327:569, 1992 (letter)
N Engl J Med. 1992 Aug 20;327(8):569-70.
� � � � � � � � � � � � � � � � �
7/1995 – Transcriptional upregulation of TGF-α by phenylacetate and PHENYLBUTYRATE is associated with differentiation of human melanoma cells.
http://www.ncbi.nlm.nih.gov/m/pubmed/7578983/
Liu L., Hudgins W. R., Miller A. C., Chen L. C., SAMID D.
http://www.sciencedirect.com/science/article/pii/S1043466685700610
Cytokine, 7: 449-456, 1995.
Cytokine Volume 7, Issue 5, July 1995, Pages 449–456
Cytokine. 1995 Jul;7(5):449-56.
a Clinical Pharmacology Branch, National Cancer Institute, Armed Forces of Radiation Research Institute, Bethesda, Maryland, USA
b Radiation Biochemistry Department, Armed Forces of Radiation Research Institute, Bethesda, Maryland, USA
http://dx.doi.org/10.1006/cyto.1995.0061
� � � � � � � � � � � � � � � � �
8/23/1996 – Activation of the human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogues.
http://www.ncbi.nlm.nih.gov/m/pubmed/8759039/
Pineau T., Hudgins W. R., Liu L., Chen L. C., Sher T., Gonzalez F. J., SAMID D.
http://www.sciencedirect.com/science/article/pii/0006295296003401
Biochem. Pharmacol., 52: 659-667, 1996.
Biochemical Pharmacology
Volume 52, Issue 4, 23 August 1996, Pages 659–667
Biochem Pharmacol. 1996 Aug 23;52(4):659-67.
∗ Laboratory of Molecular Carcinogenesis U.S.A.
‡ Clinical Pharmacology Branch, National Cancer Institute, Bethesda, MD U.S.A.
§ Experimental Therapeutics Program, University of Virginia Cancer Center, Charlottesville, VA, U.S.A.
http://dx.doi.org/10.1016/0006-2952(96)00340-1
This work was supported, in part, by funds from the Elan Pharmaceutical Research Corporation through a Cooperative Research and Development Agreement (CACR-0139).
� � � � � � � � � � � � � � � � �
9/1996 – The differentiating agent phenylacetate increases prostate-specific antigen production by prostate cancer cells.
http://www.ncbi.nlm.nih.gov/m/pubmed/8827086/
Walls R., Thibault A., Liu L., Wood C., Kozlowski J. M., Figg W. D., Sampson M. L., Elin R. J., SAMID D.
Prostate, 29: 177-182, 1996.
Prostate. 1996 Sep;29(3):177-82.
Clinical Pharmacology Branch, National Cancer Institute, Bethesda, Maryland, USA.
� � � � � � � � � � � � � � � � �
10/25/1996 – Transcriptional upregulation of γ globin by PHENYLBUTYRATE and analogous aromatic fatty acids.
http://www.ncbi.nlm.nih.gov/m/pubmed/8937430/
Hudgins W. R., Fibach E., Safaya S., Rieder R. F., Miller A. C., SAMID D.
http://www.sciencedirect.com/science/article/pii/0006295296004765
Biochem. Pharmacol., 52: 1227-1233, 1996.
Biochem Pharmacol. 1996 Oct 25;52(8):1227-33.
Biochemical Pharmacology
Volume 52, Issue 8, 25 October 1996, Pages 1227–1233
a Clinical Pharmacology Branch, National Cancer Institute, and Laboratory of Chemical Biology, National Institute of Diabetes, Digestive Diseases and Kidney Diseases, National Institutes Of Health, Bethesda, MD, U.S.A.
b Department of Hematology, Hadassah University Hospital, Jerusalem, Israel
c Department of Medicine, State University of New York Health Science Center, Brooklyn, NY, U.S.A.
d Radiation Biochemistry Department, Armed Forces Radiation Research Institute, Bethesda, MD, U.S.A.
e University of Virginia Cancer Center, Charlottesville, VA, U.S.A.
http://dx.doi.org/10.1016/0006-2952(96)00476-5

This work was supported by funds from the Elan Pharmaceutical Research Corp. and from the Israeli Science Foundation, administered by the Israel Academy of Sciences and Humanities.
� � � � � � � � � � � � � � � � �
1997 – The nuclear receptors PPARS as novel targets in differentiation therapy: activation by phenylacetate and PHENYLBUTYRATE .
SAMID D., Wells M., Kulkarni M., Lei L., Thibault A.
Anticancer Res., 17: 3927-3928, 1997.
� � � � � � � � � � � � � � � � �
8/2001 – A phase Idose escalation and bioavailability study of oral sodium PHENYLBUTYRATE in patients with refractory solid tumor malignancies
http://www.ncbi.nlm.nih.gov/m/pubmed/11489804
J Gilbert, S D Baker, … M A Carducci
http://m.clincancerres.aacrjournals.org/content/7/8/2292.long
Clin Cancer Res 7(8):2292-300 (2001), PMID.11489804

Clin Cancer Res. 2001 Aug;7(8):2292-300

References:

2. ↵ Liu L., Hudgins W. R., Miller A. C., Chen L. C., SAMID D. Transcriptional upregulation of TGF-α by phenylacetate and PHENYLBUTYRATE is associated with differentiation of human melanoma cells. Cytokine, 7: 449-456, 1995.
http://www.ncbi.nlm.nih.gov/m/pubmed/7578983/

http://www.sciencedirect.com/science/article/pii/S1043466685700610
3. ↵ Hudgins W. R., Fibach E., Safaya S., Rieder R. F., Miller A. C., SAMID D. Transcriptional upregulation of γ globin by PHENYLBUTYRATE and analogous aromatic fatty acids. Biochem. Pharmacol., 52: 1227-1233, 1996.
http://www.ncbi.nlm.nih.gov/m/pubmed/8937430/

http://www.sciencedirect.com/science/article/pii/0006295296004765
5. ↵ SAMID D., Shack S., Myers C. E. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate. J. Clin. Investig., 91: 2288-2295, 1991.
http://www.ncbi.nlm.nih.gov/m/pubmed/8486788/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC288233/

http://m.jci.org/articles/view/116457
6. ↵ Pineau T., Hudgins W. R., Liu L., Chen L. C., Sher T., Gonzalez F. J., SAMID D. Activation of the human peroxisome proliferator-activated receptor by the antitumor agent phenylacetate and its analogues. Biochem. Pharmacol., 52: 659-667, 1996.
http://www.ncbi.nlm.nih.gov/m/pubmed/8759039/

http://www.sciencedirect.com/science/article/pii/0006295296003401
15. ↵ Walls R., Thibault A., Liu L., Wood C., Kozlowski J. M., Figg W. D., Sampson M. L., Elin R. J., SAMID D. The differentiating agent phenylacetate increases prostate-specific antigen production by prostate cancer cells. Prostate, 29: 177-182, 1996.
http://www.ncbi.nlm.nih.gov/m/pubmed/8827086/
20. ↵ SAMID D., Wells M., Kulkarni M., Lei L., Thibault A. The nuclear receptors PPARS as novel targets in differentiation therapy: activation by phenylacetate and PHENYLBUTYRATE. Anticancer Res., 17: 3927-3928, 1997.
� � � � � � � � � � � � � � � � �
10/2001 – A Phase I clinical and pharmacological evaluation of sodium PHENYLBUTYRATE on an 120-h infusion schedule
M A Carducci, J Gilbert, … R C Donehower
Clin Cancer Res 7(10):3047-55 (2001), PMID.11595694
http://www.ncbi.nlm.nih.gov/m/pubmed/11595694
Clin Cancer Res. 2001 Oct;7(10):3047-55.
http://m.clincancerres.aacrjournals.org/content/7/10/3047.long
Division of Medical Oncology, The Johns Hopkins Oncology Center, Baltimore, MD, USA.

References:

10. ↵ SAMID D., Shack S., Myers C. E. Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate. J. Clin. Investig., 91: 2288-2295, 1991.
http://www.ncbi.nlm.nih.gov/m/pubmed/8486788/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC288233/

http://m.jci.org/articles/view/116457

http://m.jci.org/articles/view/116457/pdf.mobile
11. ↵ SAMID D., Shack S., Sherman L. T. Phenylacetate:

a novel nontoxic inducer of tumor cell differentiation. Cancer Res., 52: 1988-1992, 1992.
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/

http://m.cancerres.aacrjournals.org/content/52/7/1988.abstract

http://m.cancerres.aacrjournals.org/content/52/7/1988.full.pdf

http://cancerres.aacrjournals.org/content/52/7/1988
13. ↵ Shack S., Miller A., Liu L., Prasanna P., Thilbault A., SAMID D. Vulnerability of multi-drug resistant tumor cells to the aromatic fatty acids phenylacetate and PHENYLBUTYRATE. Clin. Cancer Res., 2: 865-872, 1996.
http://www.ncbi.nlm.nih.gov/m/pubmed/9816242/

http://m.clincancerres.aacrjournals.org/content/2/5/865.abstract

http://m.clincancerres.aacrjournals.org/content/2/5/865.full.pdf

http://clincancerres.aacrjournals.org/content/2/5/865
14. ↵ SAMID D., Yeh A., Prasanna P. Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate. Blood, 80: 1576-1581, 1992.
http://www.ncbi.nlm.nih.gov/m/pubmed/1381630/

http://m.bloodjournal.hematologylibrary.org/content/80/6/1576.abstract

http://m.bloodjournal.hematologylibrary.org/content/80/6/1576.full.pdf
17. ↵ SAMID D., Ram Z., Hudgins W. R., Shack S., Liu L., Walbridge S., Oldfield E. H., Myers C. E. Selective activity of phenylacetate against malignant gliomas:

resemblance to fetal brain damage in phenylketonuria. Cancer Res., 54: 891-895, 1994.
http://www.ncbi.nlm.nih.gov/m/pubmed/8313377/

http://cancerres.aacrjournals.org/content/54/4/891/
18. ↵ Fibach E., Prasanna P., Rodgers G. P., SAMID D. Enhanced fetal hemoglobin production by phenylacetate and 4-PHENYLBUTYRATE in erythroid precursors derived from normal donors and patients with sickle cell anemia and β-thalassemia. Blood, 82: 2203-2209, 1993.
http://www.ncbi.nlm.nih.gov/m/pubmed/7691251/

http://m.bloodjournal.hematologylibrary.org/content/82/7/2203.abstract

http://m.bloodjournal.hematologylibrary.org/content/82/7/2203.full.pdf
23. ↵ Liu L., Hudgins W. R., Miller A. C., Chen L. C., SAMID D. Transcriptional upregulation of TGF-α by phenylacetate and PHENYLBUTYRATE is associated with differentiation of human melanoma cells. Cytokine, 7: 449-456, 1995.
http://www.ncbi.nlm.nih.gov/m/pubmed/7578983/

http://www.sciencedirect.com/science/article/pii/S1043466685700610
24. ↵ Hudgins W. R., Fibach E., Safaya S., Reider R. F., Miller A. C., SAMID D. Transcriptional upregulation of γ globin by PHENYLBUTYRATE and analogous aromatic fatty acids. Biochem. Pharmacol., 52: 1227-1233, 1996.
http://www.ncbi.nlm.nih.gov/m/pubmed/8937430/

http://www.sciencedirect.com/science/article/pii/0006295296004765
27. ↵ Pineau T., Hudgins W. R., Liu L., Chen L. C., Sher T., Gonzalez F. J., SAMID D. Activation of human peroxisome proliferator activator receptor by the antitumor agent phenylacetate and its analogs. Biochem. Pharmacol., 52: 659-667, 1996.
http://www.ncbi.nlm.nih.gov/m/pubmed/8759039/

http://www.sciencedirect.com/science/article/pii/0006295296003401
33. ↵ Walls R., Thilbault A., Liu L., Wood C., Kozlowski J. M., Figg W. D., Sampson M. L., Elin R. J., SAMID D. The differentiating agent phenylacetate increases prostate-specific antigen production by prostate cancer cells. Prostate, 29: 177-182, 1996.
http://www.ncbi.nlm.nih.gov/m/pubmed/8827086/
40. ↵ Thibault A., Cooper M. R., Figg W. D., Venzon D. J., Sartor A. O., Tompkins A. C., Weinberger M S., Headlee D. J., McCall N. A., SAMID D., et al A phase I and pharmacokinetic study of intravenous phenylacetate in patients with cancer. Cancer Res., 54: 1690-1694, 1994.
http://www.ncbi.nlm.nih.gov/m/pubmed/8137283/

http://m.cancerres.aacrjournals.org/content/54/7/1690.abstract

http://m.cancerres.aacrjournals.org/content/54/7/1690.full.pdf

http://cancerres.aacrjournals.org/content/54/7/1690
41. ↵ Piscitelli S. C., Thibault A., Figg W. D., Tompkins A. C., Headlee D., Lieberman R., SAMID D., Myers C. E. Disposition of PHENYLBUTYRATE and its metabolites, phenylacetate and phenylacetylglutamine. J. Clin. Pharmacol., 35: 368-373, 1995.
http://www.ncbi.nlm.nih.gov/m/pubmed/7650225/

http://onlinelibrary.wiley.com/doi/10.1002/j.1552-4604.1995.tb04075.x/abstract;jsessionid=43600D49608A093971D675F3DB5FF13D.d01t03
47. ↵ SAMID D., Wells M., Kulkarni M., Lei L., Thibault A. The nuclear receptors PPARS as novel targets in differentiation therapy:

activation by phenylacetate and PHENYLBUTYRATE. Anticancer Res., 17: 3927-3928, 1997
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4/2005 – Oral sodium PHENYLBUTYRATE in patients with recurrent malignant gliomas:

A dose escalation and pharmacologic study

Neuro-oncol. 2005 April; 7(2): 177–182 PMCID: PMC1871887

PDF:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1871887/pdf/neu0702p177.pdf
References:

3. Buckner JC, Malkin MG, Reed E, Cascino TL, Reid JM, Ames MM, Tong WP, Lim S, Figg WD

Phase II study of anti-neoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma

Mayo Clin Proc. 1999;74:137–145

12. Gore SD, SAMID D, Weng LJ

Impact of the putative differentiating agents sodium PHENYLBUTYRATE and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells

Clin Cancer Res. 1997a;3:1755–1762

17. Hudgins WR, Pineau T, Sher T, Gonzales FJ, Myers CE, SAMID D

Anticancer activity of phenylacetate and related aromatic fatty acids:

Correlation with lipophilicity and capacity to activate nuclear receptor

Proc Am Assoc Can Res. 1994;35:391. (abstract 2332)

19. SAMID D, Shack S, Myers CE

Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate

J Clin Invest. 1993;91:2288–2295

20. SAMID D, Ram Z, Hudgins WR, Shack S, Liu L, Walbridge S, Oldfield EH, Myers CE

Selective activity of phenylacetate against malignant gliomas:

Resemblance to fetal brain damage in phenylketonuria

Cancer Res. 1994;54:891–895

21. Sidell N, Wada R, Han G, Chang B, Shack S, Moore T, SAMID D

Phenylacetate synergizes with retinoic acid in inducing the differentiation of human neuroblastoma cells

Int J Cancer. 1995;60:507–514
� � � � � � � � � � � � � � � � �
4/2005 – Oral sodium PHENYLBUTYRATE in patients with recurrent malignant gliomas:

A dose escalation and pharmacologic study

Neuro-oncol. 2005 April; 7(2): 177–182 PMCID: PMC1871887

PDF:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1871887/pdf/neu0702p177.pdf
References:

3. Buckner JC, Malkin MG, Reed E, Cascino TL, Reid JM, Ames MM, Tong WP, Lim S, Figg WD
http://www.ncbi.nlm.nih.gov/m/pubmed/10069350
Phase II study of anti-neoplastons A10 (NSC 648539) and AS2-1 (NSC 620261) in patients with recurrent glioma
http://www.mayoclinicproceedings.org/article/S0025-6196(11)63835-4/fulltext
Mayo Clin Proc. 1999;74:137–145
http://linkinghub.elsevier.com/retrieve/pii/S0025-6196(11)63835-4
Mayo Clinic Proceedings
http://www.sciencedirect.com/science/article/pii/S0025619611638354
Mayo Clin Proc 74(2):9 (1999)
http://download.journals.elsevierhealth.com/pdfs/journals/0025-6196/PIIS0025619611638354.pdf
DOI: 10.4065/74.2.137
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2003.01098.x/full
Mayo Clin Proc 1999; 74: 137–45
http://onlinelibrary.wiley.com/doi/10.1046/j.1365-2796.2003.01098.x/references

http://onlinelibrary.wiley.com/store/10.1046/j.1365-2796.2003.01098.x/asset/j.1365-2796.2003.01098.x.pdf?v=1&t=hbs6xce2&s=3423e3cd1955667e8e8cdf33323faf0bd85b6a29

http://onlinelibrary.wiley.com/store/10.1046/j.1365-2796.2003.01098.x/asset/j.1365-2796.2003.01098.x.pdf?v=1&t=hbrndkdf&s=e0af2d3bfb13841852d92a839d3a4932a5f4bb48
12. Gore SD, SAMID D, Weng LJ

Impact of the putative differentiating agents sodium PHENYLBUTYRATE and sodium phenylacetate on proliferation, differentiation, and apoptosis of primary neoplastic myeloid cells

Clin Cancer Res. 1997a;3:1755–1762
http://www.ncbi.nlm.nih.gov/m/pubmed/9815560/

http://m.clincancerres.aacrjournals.org/content/3/10/1755.abstract

http://m.clincancerres.aacrjournals.org/content/3/10/1755.full.pdf

http://clincancerres.aacrjournals.org/content/3/10/1755
17. Hudgins WR, Pineau T, Sher T, Gonzales FJ, Myers CE, SAMID D

Anticancer activity of phenylacetate and related aromatic fatty acids:

Correlation with lipophilicity and capacity to activate nuclear receptor

Proc Am Assoc Can Res. 1994;35:391. (abstract 2332)

19. SAMID D, Shack S, Myers CE

Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate

J Clin Invest. 1993;91:2288–2295
http://www.ncbi.nlm.nih.gov/m/pubmed/8486788/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC288233/

http://m.jci.org/articles/view/116457
20. SAMID D, Ram Z, Hudgins WR, Shack S, Liu L, Walbridge S, Oldfield EH, Myers CE

Selective activity of phenylacetate against malignant gliomas:

Resemblance to fetal brain damage in phenylketonuria

Cancer Res. 1994;54:891–895
http://www.ncbi.nlm.nih.gov/m/pubmed/8313377/

http://cancerres.aacrjournals.org/content/54/4/891
21. Sidell N, Wada R, Han G, Chang B, Shack S, Moore T, SAMID D

Phenylacetate synergizes with retinoic acid in inducing the differentiation of human neuroblastoma cells

Int J Cancer. 1995;60:507–514
http://www.ncbi.nlm.nih.gov/m/pubmed/7829265/
� � � � � � � � � � � � � � � � �
4/2007Phase I dose escalation clinical trial of PHENYLBUTYRATE sodium administered twice daily to patients with advanced solid tumors
Luis H LH Camacho, Jon J Olson, … Mark G MG Malkin
Invest New Drugs 25(2):131-8 (2007), PMID.17053987

Investigational New Drugs
April 2007, Volume 25, Issue 2, pp 131-138
http://www.ncbi.nlm.nih.gov/m/pubmed/17053987

http://link.springer.com/article/10.1007%2Fs10637-006-9017-4
References:

4. SAMID D, Shack S, Sherman LT

(1992)

Phenylacetate:

a novel nontoxic inducer of tumor cell differentiation

Cancer Res 52(7):1988–1992
http://www.ncbi.nlm.nih.gov/m/pubmed/1372534/
Cancer Res 52:1988,1992
Cancer Res. 1992 Apr 1;52(7):1988-92.
http://cancerres.aacrjournals.org/content/52/7/1988
5. DiGiuseppe JA, Weng LJ, Yu KH, Fu S, Kastan MB, SAMID D, et al

(1999)

PHENYLBUTYRATE-induced G1 arrest and apoptosis in myeloid leukemia cells:

structure-function analysis

Leukemia 13(8):1243–1253
http://www.ncbi.nlm.nih.gov/m/pubmed/10450753/
7. SAMID D, Hudgins WR, Shack S, Liu L, Prasanna P, Myers CE

(1997)

Phenylacetate and PHENYLBUTYRATE as novel, nontoxic differentiation inducers

Adv Exp Med Biol 400A:501–505
http://www.ncbi.nlm.nih.gov/m/pubmed/9547596/
20. Boudoulas S, Lush RM, McCall NA, SAMID D, Reed E, Figg WD

(1996)

Plasma protein binding of phenylacetate and PHENYLBUTYRATE, two novel antineoplastic agents

Ther Drug Monit 18(6):714–720
http://www.ncbi.nlm.nih.gov/m/pubmed/8946671/
24. Thibault A, SAMID D, Cooper MR, Figg WD, Tompkins AC, Patronas N, et al

(1995)

Phase I study of phenylacetate administered twice daily to patients with cancer

Cancer 75(12):2932–2938
http://www.ncbi.nlm.nih.gov/m/pubmed/7773944/
30. Stockhammer G, Manley GT, Johnson R, Rosenblum MK, SAMID D, Lieberman FS

(1995)

Inhibition of proliferation and induction of differentiation in medulloblastoma- and astrocytoma-derived cell lines with phenylacetate

J Neurosurg 83(4):672–681
http://www.ncbi.nlm.nih.gov/m/pubmed/7674018/
32. Ram Z, SAMID D, Walbridge S, Oshiro EM, Viola JJ, Tao-Cheng JH, et al

(1994)

Growth inhibition, tumor maturation, and extended survival in experimental brain tumors in rats treated with phenylacetate

Cancer Res 54(11):2923–2927
http://www.ncbi.nlm.nih.gov/m/pubmed/8187079/

http://m.cancerres.aacrjournals.org/content/54/11/2923.full.pdf

http://m.cancerres.aacrjournals.org/content/54/11/2923.abstract

http://cancerres.aacrjournals.org/content/54/11/2923
33. SAMID D, Yeh TJ, Shack S

(1991)

Interferon in combination with antitumourigenic phenyl derivatives: potentiation of IFN alpha activity in-vitro

Br J Haematol 79(Suppl 1):81–83
http://www.ncbi.nlm.nih.gov/m/pubmed/1931716/
34. Gorospe M, Shack S, Guyton KZ, SAMID D, Holbrook NJ

(1996)

Up-regulation and functional role of p21Waf1/Cip1 during growth arrest of human breast carcinoma MCF-7 cells by phenylacetate

Cell Growth Differ 7(12):1609–1615
http://www.ncbi.nlm.nih.gov/m/pubmed/8959328/
35. Bar-Ner M, Thibault A, Tsokos M, Magrath IT, SAMID D

(1999)

PHENYLBUTYRATE induces cell differentiation and modulates Epstein-Barr virus gene expression in Burkitt’s lymphoma cells

Clin Cancer Res 5(6):1509–1516
http://www.ncbi.nlm.nih.gov/m/pubmed/10389940/

http://m.clincancerres.aacrjournals.org/content/5/6/1509.abstract

http://m.clincancerres.aacrjournals.org/content/5/6/1509.long

http://clincancerres.aacrjournals.org/content/5/6/1509
36. Shack S, Miller A, Liu L, Prasanna P, Thibault A, SAMID D

(1996)

Vulnerability of multidrug-resistant tumor cells to the aromatic fatty acids phenylacetate and PHENYLBUTYRATE

Clin Cancer Res 2(5):865–872
http://www.ncbi.nlm.nih.gov/m/pubmed/9816242/

http://m.clincancerres.aacrjournals.org/content/2/5/865.abstract

http://m.clincancerres.aacrjournals.org/content/2/5/865.full.pdf

http://clincancerres.aacrjournals.org/content/2/5/865
37. SAMID D, Yeh A, Prasanna P

(1992)

Induction of erythroid differentiation and fetal hemoglobin production in human leukemic cells treated with phenylacetate

Blood 80(6):1576–1581
http://www.ncbi.nlm.nih.gov/m/pubmed/1381630/

http://m.bloodjournal.hematologylibrary.org/content/80/6/1576.abstract

http://m.bloodjournal.hematologylibrary.org/content/80/6/1576.full.pdf
38. Fibach E, Prasanna P, Rodgers GP, SAMID D

(1993)

Enhanced fetal hemoglobin production by phenylacetate and 4-PHENYLBUTYRATE in erythroid precursors derived from normal donors and patients with sickle cell anemia and beta-thalassemia

Blood 82(7):2203–2209
http://www.ncbi.nlm.nih.gov/m/pubmed/7691251/

http://m.bloodjournal.hematologylibrary.org/content/82/7/2203.abstract

http://m.bloodjournal.hematologylibrary.org/content/82/7/2203.full.pdf
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4/2009Phase 2 study of sodium PHENYLBUTYRATE in ALS.
Merit E Cudkowicz, Patricia L Andres, … THE NORTHEAST ALS AND THE NATIONAL VA ALS RESEARCH CONSORTIUMS
Amyotroph Lateral Scler 10(2):99-106 (2009), PMID.18688762
Amyotroph Lateral Scler. 2009 Apr;10(2):99-106. doi: 10.1080/17482960802320487
http://www.ncbi.nlm.nih.gov/m/pubmed/18688762

http://informahealthcare.com/doi/pdf/10.1080/17482960802320487?noFrame=true

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1871887
� � � � � � � � � � � � � � � � �
10/1/2009 – A Phase I Dose-Finding Study of 5-Azacytidine in Combination with Sodium PHENYBUTYRATE in Patients with Refractory Solid Tumors
J Lin, J Gilbert, … M A Carducci
Clin Cancer Res 15(19):6241-6249 (2009), PMID.19789320, PMCID PMC2845396
Clin Cancer Res. 2009 Oct 1;15(19):6241-9. doi: 10.1158/1078-0432.CCR-09-0567. Epub 2009 Sep 29
http://www.ncbi.nlm.nih.gov/m/pubmed/19789320

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2845396
References:

24. Robertson KD, Hayward SD, Ling PD, SAMID D, Ambinder RF

Transcriptional activation of the Epstein-Barr virus latency C promoter after 5-azacytidine treatment:

evidence that demethylation at a single CpG site is crucial

Mol Cell Biol. 1995;15:6150–9
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC230866/
� � � � � � � � � � � � � � � � �
7/2010Phase 2 comparison of a novel ammonia scavenging agent with sodium PHENYLBUTYRATE in patients with urea cycle disorders:

Safety, pharmacokinetics and ammonia control
http://www.ncbi.nlm.nih.gov/m/pubmed/20382058/
Brendan Lee, William Rhead, … Susan A Berry
Mol Genet Metab 100(3):8 (2010), PMID.20382058, PMCID PMC2905228
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905228/
Mol Genet Metab. 2010 Jul;100(3):221-8. doi: 10.1016/j.ymgme.2010.03.014. Epub 2010 Mar 23.
Baylor College of Medicine, Houston, TX, USA.

http://www.sciencedirect.com/science/article/pii/S1096719210001058
a Baylor College of Medicine, Houston, TX, United States
b Howard Hughes Medical Institute, TX, United States
c Pediatrics, Medical College of Wisconsin, Milwaukee, WI, United States
d Mount Sinai School of Medicine, New York, NY, United States
e Hyperion Therapeutics, Inc., South San Francisco, CA, United States
f Pharsight Corp., Montreal, Quebec, Canada
g Chiltern, Wilmington, NC, United States
h Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, United States
http://dx.doi.org/10.1016/j.ymgme.2010.03.014

Antineoplastons: Phenylacetylglutaminate (PG or PAG), Phenylacetate (PN), and Phenylbutyrate (PB)

PHENYLACETYLGLUTAMINATE (PAG or PG) and PHENYLACETATE (PN) are metabolites of PHENYLBUTYRATE (PB) and are constituents of antineoplaston AS2-1
� � � � � � � � � � � � � � � �
Antineoplastons AS2-1 and AS2-5 are DERIVED FROM A10
� � � � � � � � � � � � � � � �
AS2-1 = 4:1 mixture of PHENYLACETIC ACID (PA) and PHENYLACETYLGLUTAMINE (PAG or PG)
� � � � � � � � � � � � � � � �
Antineoplaston AS2-5 = PHENYLACETYLGLUTAMINE (PAG or PG)
� � � � � � � � � � � � � � � �
National Cancer Institute (NCI) at the National Institutes of Health (NIH)
Antineoplastons
General Information: http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page2
� � � � � � � � � � � � � � � �
http://www.burzynskiclinic.com/scientific-publications.html
Review Articles on Clinical Trials:

1. 3/2004

Burzynski, S.R. The Present State of Antineoplaston Research. Integrative Cancer Therapies 2004;3:47-58.
http://www.burzynskiclinic.com/images/stories/Publications/994.pdf
Volume 3 Number 1 March 2004
DOI: 10.1177/1534735403261964

Pg. 48

Antineoplaston A2, which contributed to the highest number of complete responses in phase I clinical studies, was elected for final purification, isolation of active components, and structure determination.
Active ingredient identified as:
3-phenylacetylamino-2, 6-piperidinedione
and was named
antineoplaston A10. [27]

27. Burzynski SR, Hendry LB, Mohabbat MO, et al. Purification of structure determination, synthesis and animal toxicity studies of antineoplaston A10. In: Proceedings of the 13th International Congress of Chemotherapy. Vienna, Austria; 1983:17, PS. 12.4 11-4.

A10 has been reproduced by synthesis involving condensation of:
1-glutamine
with
phenylacetyl chloride
and subsequent cyclization of
phenylacetylglutamine (PG). [28]

28. Burzynski SR, Hai TT. Antineoplaston A10. Drugs of the Future. 1985;10:103-105.

Metabolism of A10 in human body yields:
phenylacetylglutamine (PG)
phenylacetylisoglutamine (isoPG)
phenylacetate (PN)
which were reproduced synthetically and formulated into:
antineoplaston
A10 injections (A10-I)
AS2-1
AS5
AS-25
[29-33]

29. Burzynski SR. Synthetic antineoplastons and analogs. Drugs of the Future. 1986;11:679-688.

30. Burzynski SR, Mohabbat MO, Lee SS. Preclinical studies of antineoplaston AS1-1 and antineoplaston AS2-5. Drugs Exptl Clin Res. 1986;12(suppl 1):11-16.
http://www.ncbi.nlm.nih.gov/pubmed/3743376/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743376/
31. Burzynski SR, Khalid M. Antineoplaston A10 injections. Drugs of the Future. 1986;11:364-365.

32. Burzynski SR, Khalid M. Antineoplaston AS2-1. Drugs of the Future. 1986;11:361-363.

33. Burzynski SR. Antineoplaston AS2-5.. Annual Drug Data Report. 1986;8-319.

These formulations were submitted for basic research and phase I clinical studies. [34-44]

34. Burzynski SR, Mohabbat MO, Burzynski B. Animal toxicology studies on oral formulation of antineoplaston A10. Drug Exptl Clin Res. 1984;10:113-118.

35. Burzynski SR. Phase I clinical studies of antineoplaston AS2-5 injections. In: Ishigami J, ed. Recent Advances in Chemotherapy. Tokyo, Japan: University of Tokyo Press; 1985.

36. Burzynski SR, Burzynski B, Mohabbat MO. Toxicology studies of antineoplaston AS 2-1 injections in cancer patients. Drugs Exptl Clin Res. 1986;12(suppl 1):25-35.
http://www.ncbi.nlm.nih.gov/pubmed/3743378/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743378/
37. Burzynski SR, Kubove E. Toxicology studies of antineoplaston A10 injections in cancer patients. Drugs Exptl Clin Res. 1986;12(suppl 1):47-55.
http://www.ncbi.nlm.nih.gov/pubmed/3743380/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743380/
38. Lehner AF, Burzynski SR, Hendry LB. 3-phenylacetylamino-2,6-piperidinedione, a naturally-occurring peptide analog with apparent antineoplastic activity may bind to DNA. Drugs Exptl Clin Res. 1986;12(suppl 1):57-72.
http://www.ncbi.nlm.nih.gov/pubmed/3743381/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743381/
39. Ashraf AQ, Liau MC, Mohabbat MO, et al. Preclinical studies of antineoplaston A10 injections. Drugs Exptl Clin Res. 1986;12(suppl 1):37-45.
http://www.ncbi.nlm.nih.gov/pubmed/3743379/

http://www.ncbi.nlm.nih.gov/m/pubmed/3743379/
40. Ashraf AQ, Liau MC, Kampalath BN, et al. Pharmacokinetic study of radioactive antineoplaston A10 following oral administration in rats. Drugs Exptl Clin Res. 1987;13(suppl 1):45-50.
http://www.ncbi.nlm.nih.gov/pubmed/3569015/

http://www.ncbi.nlm.nih.gov/m/pubmed/3569015/
41. Hendry LB, Muldoon TG, Burzynski SR et al. Stereochemical modeling studies of the interaction of Antineoplaston A10 with DNA. Drugs Exptl Clin Res. 1987;13(suppl 1):77-81.
http://www.ncbi.nlm.nih.gov/pubmed/3569020/

http://www.ncbi.nlm.nih.gov/m/pubmed/3569020/
42. Ashraf AQ, Burzynski SR. Comparative study of antineoplaston A10 levels in plasma of healthy people and cancer patients. Adv Exptl Clin Chemother. 1988;2:19-28.

43. Ashraf AQ, Kampalath BN, Burzynski SR. Pharmacokinetic analysis of antineoplaston A10 injections following intravenous administration in rats. Adv Exptl Clin Chemother. 1988;6:33-39.

44. Burzynski SR, Kubove E, Burzynski B. Phase I clinical studies of oral formulation of antineoplaston AS2-1. Adv Exptl Clin Chemother. 1988;2:29-36.

A10
A10-I
AS2-1
were selected for phase II studies.
2 initial phase II studies in
ASTROCYTOMA
and
HIGH-GRADE GLIOMA
began in
1988
and
1990
and were conducted outside investigational new drug (IND) process.

Since 1994 the FDA authorized 74 phase II studies with
A10
A10-I
AS2-1
under INDs
43,742
22,029
in advanced malignancies.

Pg. 49

Phenylacetate (PN)
is active ingredient of
antineoplaston AS2-1.

Phenylglutamine (PG)
is main ingredient of
A10-I.

Phenylglutamine (PG) exhibits antineoplastic activity across wide array of cancer cell lines.

Phenylglutamine (PG)
inhibits uptake of growth-critical amino acids, such as:
1-glutamine
and
1-leucine
in neoplastic cells.

Reduction in amino acid availability may contribute to drug’s antineoplastic activity.

Human glioma (U-87) cells rapidly take up Phenylglutamine (PG) by mechanism similar to facilitated diffusion.

Upon removal of Phenylglutamine (PG) from media, PG rapidly and completely effluxes from the cell.

Phenylglutamine (PG)
enters cells via stereospecific amino acid transporters for
1-glutamine.

Formulations of
Antineoplastons:

Antineoplastons
are a class of 12 antitumor agents.

Following synthetic antineoplaston formulations used in phase II studies.

Antineoplaston A10
capsules contain 500 mg of
3-phenylacetylamino-2, 6-piperidinedione.

Antineoplaston A10 injection
is mixture of sodium salts of
Phenylglutamine (PG)
and
Phenylacetylisoglutamine (isoPG)
in 4:1 ratio.

Available in 500 mL and 1000 mL (300 mg/mL) plastic bags.

Antineoplaston AS2-1
capsules containing 500 mg of 4:1
Phenylacetate (PN)
and
Phenylglutamine (PG).

Antineoplaston AS2-1 injection
is mixture of
Phenylacetate (PN)
and
Phenylglutamine (PG)
in 4:1 ratio.

Available in 250 mL (80 mg/mL) plastic bags.
� � � � � � � � � � � � � � � �
Interim Reports on Clinial Trials:

18. 6/2005

INTEGRATIVE CANCER THERAPIES

BT-12

CHILDREN WITH PRIMITIVE NEUROECTODERMAL TUMORS (PNET)

CAN-01

CAN-1

PATIENTS WITH REFRACTORY MALIGNANCIES

Burzynski, S.R., Weaver, R.A., Janicki, T., Szymkowski, B., Jurida, G., Khan, M., Dolgopolov, V.

Long-term survival of high-risk pediatric patients with PRIMITIVE NEUROECTODERMALTUMORS treated with Antineoplastons A10 and AS2-1
http://www.ncbi.nlm.nih.gov/pubmed/15911929
Integrative Cancer Therapies 2005;4(2):168-177
http://www.ncbi.nlm.nih.gov/m/pubmed/15911929
Integr Cancer Ther. 2005 Jun;4(2):168-77
http://www.burzynskiclinic.com/images/stories/Publications/1220.pdf
DOI: 10.1177/1534735405276835
http://m.ict.sagepub.com/content/4/2/168.long?view=long&pmid=15911929
Antineoplastons (ANP) A10 and AS2-1, which are synthetic analogs of naturally occurring derivatives of glutamine, isoglutamine, and phenylacetic acid, have shown an increasing spectrum of activity in primary brain tumors. [1]

Review Articles on Clinical Trials:

1. 3/2004

Burzynski, S.R. The Present State of Antineoplaston Research. Integrative Cancer Therapies 2004;3:47-58.
http://www.burzynskiclinic.com/images/stories/Publications/994.pdf
Volume 3 Number 1 March 2004
DOI: 10.1177/1534735403261964
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IV. Aetna considers SODIUM PHENYLBUTYRATE medically necessary for the treatment of acute promyelocytic leukemia and malignant glioma
http://www.aetna.com/cpb/medical/data/200_299/0240.html
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The FDA has approved SODIUM PHENYLBUTYRATE as a treatment to remove ammonia from the bloodstream in individuals with urea cycle disorders
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SODIUM PHENYLBUTYRATE was given an orphan drug designation by the FDA for use as an adjunct to surgery, radiation therapy, and chemotherapy for treatment of individuals with primary or recurrent malignant glioma
http://www.anthem.com/medicalpolicies/policies/mp_pw_a050524.htm
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Cumulative List of all Products that have received Orphan Designation: Total active designations: 2002 Effecive: (sic – Effective:) 5/5/2009
http://www.fda.gov/downloads/forindustry/developingproductsforrarediseasesconditions/howtoapplyfororphanproductdesignation/ucm162066.xls
PHENYLBUTYRATE (PB) and SODIUM PHENYLBUTYRATE are listed alphabetically in the lower 1/4th of this document
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Sodium Phenylbutyrate (PB)
Year – Pubmed (110 entries)
1958 1st entry
1995 1st clinical trial
2001 Phase 1
2009 Phase 2
2012 Phase 3
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Phenylacetate (PN)
Year – Pubmed (29,686 entries)
1883 1st entry
1994 Phase 1
1999 Phase 2
2013 latest
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Antineoplaston(s)
Year – Pubmed (88 entries)
1976 1st entry
1986 Phase 1
1999 Phase 2
2003 Phase 2 preliminary
2004 Phase 2 preliminary
2012 latest
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National Cancer Institute (NCI) at the National Institutes of Health (NIH)
Antineoplastons (PDQ®) Overview:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page1

http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/patient
General Information:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page2
History:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page3
Laboratory/Animal/Preclinical Studies:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page4
Human/Clinical Studies:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page5
Adverse Effects:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page6
Summary of the Evidence for Antineoplastons:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page7
Changes to This Summary:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page8
About This PDQ Summary:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/healthprofessional/page9
Questions and Answers About Antineoplastons:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/patient/page2
Current Clinical Trials:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/patient/page3
Changes to This Summary:
http://www.cancer.gov/cancertopics/pdq/cam/antineoplastons/patient/page4