WO1987003481A1 - Anthracycline type antitumor agents with l-ascorbic acid - Google Patents

Anthracycline type antitumor agents with l-ascorbic acid Download PDF

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Publication number
WO1987003481A1
WO1987003481A1 PCT/US1986/002646 US8602646W WO8703481A1 WO 1987003481 A1 WO1987003481 A1 WO 1987003481A1 US 8602646 W US8602646 W US 8602646W WO 8703481 A1 WO8703481 A1 WO 8703481A1
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WIPO (PCT)
Prior art keywords
ascorbic acid
antitumor
ratio
antitumor agents
anthracycline
Prior art date
Application number
PCT/US1986/002646
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French (fr)
Inventor
Robert W. Veltri
Original Assignee
American Biotechnology Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Biotechnology Co., Ltd. filed Critical American Biotechnology Co., Ltd.
Publication of WO1987003481A1 publication Critical patent/WO1987003481A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof

Definitions

  • This invention relates to novel selected mixtures of anthracycline antitumor agents with L-ascorbic acid and their employment as antitumor agents.
  • L-ascorbic acid or Vitamin C is a well known physiologically active agent originally isolated by Szent- Gyorgyi. It has many and well known pharmaceutical activities.
  • the anthracyclines are a well known class of antitumor agents that have been employed in the clinical treatment of various tumors in humans since at least 1970.
  • the best known of the class is doxorubicin (Andriamycin) . It has a wide spectrum of antitumor activity, such activity encompasing a broad range of solic tumors that prior to its isolation from Streptomyces peucetius caesium had been relatively insensitive to chromatherapy, especially the soft tissue and bone sarcomas and bladder cancer.
  • the anthracyclines are further characterized by falling into two classes based on their mode of inhibition of DNA synthesis.
  • Type I anthracyclines such as aclacinomycin-A and marcellomycin, inhibit whole cellular RNA synthesis at six-seven fold lower concentrations and nucleolar preribosomal synthesis at 170-1250 fold lower concentrations than those required for inhibition of DNA synthesis.
  • Structural differences between type I and type II anthracyclines include the presence of 10-carbomethoxy group and a greater number of sugar residues in the Type II compounds. If the 10-carbomethoxy group is removed, the ability to inhibit nucleolar RNA synthesis is decreased and their is a loss of antitumor activity. Removal of sugar residues can also cause a loss of selectivity of the anthracyclines.
  • This invention is concerned with Type I anthracyclines exemplified by doxorubicin, carminomycin and dihydroxy anthracenedione (Mitoxantrone) or its diacetate (DHAQ diacetate) .
  • the anthracyclines are unique amongst clinical antitumor agents in that many of them including those presently believed to be the most active, have toxic effects which are dose related.
  • the major toxicities are myelosuppression including cardiotoxicity in approximately 60 to 80% of the patients, stomatitis in as many as 80%, nausea and/or vomiting in 20 to 55%, and alopecia in virtually all cases.
  • the art has attempted to circumscribe the toxicity of doxorubicin and other anthracyclines by limiting the dose. Such efforts have included coadministration with other chemotherapeutic agents, preparation of homologs, and intermittent administration of the drug. Some degree of success has been achieved with these procedures, but there is room for improvement. The art has sought methods for increasing the efficacy of a particular doses or for making possible the administration of the same or larger doses over longer periods of time without triggering a toxic response.
  • SUBSTITUTE SHEET tested combinations of adriamycin, ascorbic acid and dimethyl sulfoxide and concluded that the combinations did not alter the effectiveness of adriamycin.
  • anthracycline Type I antitumor agents together with anthracycline Type I antitumor agents are effective to improve the efficacy of the selected antitumor agent provided that the correct amounts of each component of the mixture are selected.
  • compositions of this invention not only reduce the toxicity of anthracycline Type I antitumor agents, but also increase the antitumor activity of the therapeutic agent.
  • the parts by weight ratio of ascorbic acid to antitumor agent will vary with the selected antitumor agents in the
  • compositions of the invention Generally it will vary from about 20:1 to 440:1 in compositions having antitumor activity which is greater than that of the same amount of antitumor agent alone.
  • the observation which forms the basis of this selective invention is the recognition that
  • the effective ratio of L-ascorbic acid to antitumor agent v depends upon the selected antitumor agent.
  • doxorubicin With doxorubicin the ratio for improved activity is about 20:1 to 175:1, the preferred ratio being 85:1 to 90:1.
  • DHAQ-diacetate dihydroxy anthracenedione diacetate
  • SUBSTITUTE SHEET respective ratios are about 55:1 to 440:1 and 220:1 to 230:1. Below these ratios the desired effect is not achieved. Above these ratios the toxicity of the antitumor agent is unacceptably high even in the presence of L- ascorbic acid.
  • P-388 is an ascites tumor administered at a concentration of 1,000,000 cells via the intraperitoneal
  • the drugs were given via the NCI's recommended intermittent schedule by I.P. injection of P-388 or L-1210 ascites tumor cells on day zero.
  • mice were treated with a mixture of L-ascorbic (200 mM) and doxorubicin.
  • the doxorubicin powder was reconstituted in 200 mM of the L-ascorbic acid in 0.85% saline to an equivalent concentration of 10 mg/kg body weight, calculated for 22 gram mice.
  • the positive control for P-388 was the known antitumor agent 5-fluorouracil (60 mg/kg) in 200 mM of the acid.
  • the doses of doxorubicin were prepared fresh daily.
  • L-ascorbic acid in 0.85% saline, doxorubicin in 0.85% saline and 0.85% saline served as further controls.
  • L-ascorbic acid can be used in the form of its metal salts, preferably an alkali metal salt such as sodium ascorbate, as will be recognized by those skilled in the art.
  • the pH of the mixtures employed in the invention is preferably about 7, but any pH, e.g., 6 to 8, which is neither so high or so low as to be toxic is acceptable.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Mixtures of anthracycline type antitumor agents and L-ascorbic acid are useful in the treatment of mammalian cancers when the mixtures contain selected quantities of the components.

Description

ANTHRACYCLINE TYPE ANTITUMOR AGENTS WITH L-ASCORBIC ACID
RELATED APPLICATION
This application is a continuation in part application of copending application serial number 804,922 filed December 5, 1985.
BACKGROUND OF THE INVENTION
This invention relates to novel selected mixtures of anthracycline antitumor agents with L-ascorbic acid and their employment as antitumor agents.
L-ascorbic acid or Vitamin C is a well known physiologically active agent originally isolated by Szent- Gyorgyi. It has many and well known pharmaceutical activities.
The anthracyclines are a well known class of antitumor agents that have been employed in the clinical treatment of various tumors in humans since at least 1970. The best known of the class is doxorubicin (Andriamycin) . It has a wide spectrum of antitumor activity, such activity encompasing a broad range of solic tumors that prior to its isolation from Streptomyces peucetius caesium had been relatively insensitive to chromatherapy, especially the soft tissue and bone sarcomas and bladder cancer. These activities of doxorubicin and other members of the class against various tumors have been discussed extensively by
Carter in the Journal Of The National Cancer Institute, Vol. 55, No. 6, December 1975, pages 1265 to 1274.
The anthracyclines are further characterized by falling into two classes based on their mode of inhibition of DNA synthesis. Type I anthracyclines such as aclacinomycin-A and marcellomycin, inhibit whole cellular RNA synthesis at six-seven fold lower concentrations and nucleolar preribosomal synthesis at 170-1250 fold lower concentrations than those required for inhibition of DNA synthesis. Structural differences between type I and type II anthracyclines include the presence of 10-carbomethoxy group and a greater number of sugar residues in the Type II compounds. If the 10-carbomethoxy group is removed, the ability to inhibit nucleolar RNA synthesis is decreased and their is a loss of antitumor activity. Removal of sugar residues can also cause a loss of selectivity of the anthracyclines.
This invention is concerned with Type I anthracyclines exemplified by doxorubicin, carminomycin and dihydroxy anthracenedione (Mitoxantrone) or its diacetate (DHAQ diacetate) .
The anthracyclines are unique amongst clinical antitumor agents in that many of them including those presently believed to be the most active, have toxic effects which are dose related. The major toxicities are myelosuppression including cardiotoxicity in approximately 60 to 80% of the patients, stomatitis in as many as 80%, nausea and/or vomiting in 20 to 55%, and alopecia in virtually all cases.
The art has attempted to circumscribe the toxicity of doxorubicin and other anthracyclines by limiting the dose. Such efforts have included coadministration with other chemotherapeutic agents, preparation of homologs, and intermittent administration of the drug. Some degree of success has been achieved with these procedures, but there is room for improvement. The art has sought methods for increasing the efficacy of a particular doses or for making possible the administration of the same or larger doses over longer periods of time without triggering a toxic response.
Fujita et al. Cancer Research 42,309 to 316, January 1982, tested the effect of L-ascorbic acid on the antitumor activity of doxorubicin and concluded that the ascorbate had no effect. Marian and Matkovics, Experimentia 38,573 (1982)
SUBSTITUTE SHEET tested combinations of adriamycin, ascorbic acid and dimethyl sulfoxide and concluded that the combinations did not alter the effectiveness of adriamycin.
-* It has been discovered that compositions containing
5 anthracycline Type I antitumor agents together with anthracycline Type I antitumor agents are effective to improve the efficacy of the selected antitumor agent provided that the correct amounts of each component of the mixture are selected. When this criterion is observed the
10 activity of the composition is greater than the activity of the anthracycline type antitumor agent alone. The compositions of this invention not only reduce the toxicity of anthracycline Type I antitumor agents, but also increase the antitumor activity of the therapeutic agent.
15 SUMMARY OF THE INVENTION
It has now been discovered that certain select mixtures " of L-ascorbic acid and anthracycline Type I antitumor gents are effective in the control of mammalian tumors. Such mixtures will contain sufficient anthracycline Type I 20 antitumor agent to deliver from 2 to 10 mg/kg body weight antitumor agent and from 220 to 880 mg/kg body weight L- ascorbic acid to the mammal under treatment.
The parts by weight ratio of ascorbic acid to antitumor agent will vary with the selected antitumor agents in the
25 compositions of the invention. Generally it will vary from about 20:1 to 440:1 in compositions having antitumor activity which is greater than that of the same amount of antitumor agent alone. The observation which forms the basis of this selective invention is the recognition that
30 the effective ratio of L-ascorbic acid to antitumor agent v depends upon the selected antitumor agent.
With doxorubicin the ratio for improved activity is about 20:1 to 175:1, the preferred ratio being 85:1 to 90:1. With dihydroxy anthracenedione diacetate (DHAQ-diacetate) the
SUBSTITUTE SHEET respective ratios are about 55:1 to 440:1 and 220:1 to 230:1. Below these ratios the desired effect is not achieved. Above these ratios the toxicity of the antitumor agent is unacceptably high even in the presence of L- ascorbic acid.
The activity of various mixtures within the scope of this invention were tested against the leukemia models P-388 and L-1210 in BFD mice obtained from Jackson Laboratories, Bar Harbor, Maine. P-388 is an ascites tumor administered at a concentration of 1,000,000 cells via the intraperitoneal
(I.P.) route on day zero of the experimental National Cancer Institute (NCI) protocol 1.200. L-1210 is an ascites tumor administered at a concentration of 100,000 cells via the I.P. route of experimental NCI protocol 1.100.
The drugs were given via the NCI's recommended intermittent schedule by I.P. injection of P-388 or L-1210 ascites tumor cells on day zero.
In these tests, the mice were treated with a mixture of L-ascorbic (200 mM) and doxorubicin. The doxorubicin powder was reconstituted in 200 mM of the L-ascorbic acid in 0.85% saline to an equivalent concentration of 10 mg/kg body weight, calculated for 22 gram mice. The positive control for P-388 was the known antitumor agent 5-fluorouracil (60 mg/kg) in 200 mM of the acid. The doses of doxorubicin were prepared fresh daily. L-ascorbic acid in 0.85% saline, doxorubicin in 0.85% saline and 0.85% saline served as further controls.
The results are given in the following tables. In all the cases, the T/C% were based upon calculation of the median survival time. In all cases, there were six experimental animals per group.
SUBSTITUTE SHEET TABLE I
EFFECT OF L-ASCORBIC ACID ON THE ANTIC__NCER ACTIVITY OF DOXORUBICIN VERSUS TH
P-388 LYMPHOMA IN BDF MICE
DOXORUBICIN [L-AA] T/CZ SURVIVORS (30 DAYS) mg/kg Exp #1 Exp Exp #1 Exp #2
10 mg/kg 855 285 300 (6/6) (6/6)
10 mg/kg -0- 200 205 (3/6) (2/6)
5 mg/kg 855 233 255 (2/6) (1/6)
5 mg/kg -0- 143 280 (1/6) (2/6)
2.5 mg/kg 855 180 230 (1/6) (2/6)
2.5 mg/kg -0- 186 240 (0/6) (1/6)
5-Fluorouracil
60 mg/kg 855 230 176 (0) (0) 60 mg/kg -0- 170 181 (0) (0)
Table II
EFFECT OF L-ASCORBIC ACID ON THE ANTICANCER ACTIVITY OF DOXORUBICIN VERSUS THE P-388 LYMPHOMA IN BDF MICE
DOXORUBICIN [L-aa] T/ SURVIVORS (30 DAYS) mg/kg
15 mg/kg 855 205 (0/6)
15 mg/kg -0- 161 (0/6)
10 mg/kg 855 283 (1/6)
10 mg/kg -0- 144 (0/6)
5 mg/kg 855 333 (3/6)
5 mg/kg -0- 2-5 (2/6)
SUBSTITUTE SHEET TABLE III
EFFECT OF VARIOUS CONCENTRATIONS OF L-ASCORBIC ACID UPON ANTITUMOR ACTIVITY OF DOXORUBICIN IN THE P-388 LYMPHOMA MODEL IN BDF MICE
DOXORUBICIN [L-AA] SURVIVAL T/CZ SURVIVORS SURVIVORS
MEDIAN DAY 30 DAYS 60 DAYS
10 mg/kg 0 30 250Z 3 2
10 mg/kg 50 60+ 500Z+ 4 3
10 mg/kg 100 60+ 500Z+ 4 3
10 mg/kg 200 60+ 500Z+ 4 3
10 mg/kg 400 54 450Z 5 2
0 mg/kg 0 12 — 0 0
0 mg/kg 50 10 - 0 0
0 mg/kg 100 11 - 0 0
0 mg/kg 200 11 - 0 0
0 mg/kg 400 11 0 0
The following table shows the results of a similar study with L-ascorbic acid and DHAQ-diacetate.
TABLE IV
EFFECT OF L-ASCORBIC ACID ON THE ANTICANCER ACTIVITY OF DHAQ-DIACETATE VERSUS THE P-388 LEUKEMIA IN BDF MICE
DHAQ [L-AA] T/C5 SURVIVORS (37 + DAYS) mg/kg
4 mg/kg 855 186 4/6
4 mg/kg -0- 215 5/6
2 mg/kg 855 186 4/6
2 mg/kg -0- 126 1/6
1 mg/kg 855 186 2/6
I mg/kg -0- 116 1/6
L-ascorbic acid can be used in the form of its metal salts, preferably an alkali metal salt such as sodium ascorbate, as will be recognized by those skilled in the art. The pH of the mixtures employed in the invention is preferably about 7, but any pH, e.g., 6 to 8, which is neither so high or so low as to be toxic is acceptable.
SUBSTITUTE SHEET

Claims

WHAT IS CLAIMED IS:
1. An antitumor mixture comprising L-ascorbic acid and an anthracycline Type I antitumor agent containing sufficient L-ascorbic acid and anthracycline type antitumor agent to deliver from 220 to 880 mg/kg body weight of ascorbic acid and from 2 to 10 mg/kg body weight anthracycline type antitumor agent in a parts by weight ratio of from 20:1 to 400:1, the ratio being selected so that the antitumor activity of the composition is greater than the antitumor activity of the anthracycline type antitumor agent alone.
2. A mixture as in Claim 1 wherein the antitumor agent is doxurubicin and the ratio is from about 20:1 to 175:1.
3. A mixture as in Claim 1 wherein the antitumor agent is doxurubicin and' the ratio is from 85:1 to 90:1.
4. A mixture as in Claim 1 wherein the dihydroxy anthracenedione diacetate and the ratio is about 55:1 to 440:1.
5. A mixture as in Claim 1 wherein the dihydroxy anthracenedione diacetate and the ratio is 220:1 to 230:1.
SUBSTITUTE SHEET
PCT/US1986/002646 1985-12-05 1986-12-05 Anthracycline type antitumor agents with l-ascorbic acid WO1987003481A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US80492285A 1985-12-05 1985-12-05
US804,922 1985-12-05
US93677086A 1986-12-02 1986-12-02
US936,770 1986-12-02

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988008715A1 (en) * 1987-05-11 1988-11-17 Procyte Corporation Method of tumor inhibition in warm-blooded animals
GB2224649A (en) * 1988-11-10 1990-05-16 Ssali Charles Lwanga Fusidic acid anti-viral compositions
EP0369079A1 (en) * 1988-11-18 1990-05-23 Norsk Hydro A/S Pharmaceutical compositions with anti-cancer activity and method for the treatment of cancer
WO2002020023A1 (en) * 2000-09-01 2002-03-14 Oxycal Laboratories, Inc. Methods and compositions for potentiating cancer chemotherapeutic agents

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278689A (en) * 1978-07-11 1981-07-14 American Cyanamid Company 1,4-Bis(substituted-amino)-5,8-dihydroxy-anthraquinones and leuco bases thereof
EP0154117A1 (en) * 1984-02-27 1985-09-11 American Cyanamid Company Use of 1,4 bis(substituted) anthrachinones for the manufacture of immunosuppresiva

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4278689A (en) * 1978-07-11 1981-07-14 American Cyanamid Company 1,4-Bis(substituted-amino)-5,8-dihydroxy-anthraquinones and leuco bases thereof
EP0154117A1 (en) * 1984-02-27 1985-09-11 American Cyanamid Company Use of 1,4 bis(substituted) anthrachinones for the manufacture of immunosuppresiva

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CARTER et al, Chemotherapy of Cancer, Second Edition, Johns Wiley and Sons, N.Y., N.Y. 1981 pages 58, 90-93 and 369. *
CHEM, ABSTRACTS, Vol. 97 (No.1) Abst. No. 406q issued 5 July 1982 "Potentiation of the Biological Activities of Daunomycin and Adriamycin by Ascorbic Acid and Dimethyl Sulfoxide. *
CHEM, ABSTRACTS, Vol. 99 (No.9) Abst. No. 64299f, issued 29 Aug. 1983 "Inhibition of Adriamycin Cardiotoxicity by Ascorbic Acid" *
See also references of EP0249632A4 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988008715A1 (en) * 1987-05-11 1988-11-17 Procyte Corporation Method of tumor inhibition in warm-blooded animals
GB2224649A (en) * 1988-11-10 1990-05-16 Ssali Charles Lwanga Fusidic acid anti-viral compositions
GB2224649B (en) * 1988-11-10 1992-08-26 Charles Lwanga Ssali Antiviral compositions comprising fusidic acid and l-ascorbic acid
EP0369079A1 (en) * 1988-11-18 1990-05-23 Norsk Hydro A/S Pharmaceutical compositions with anti-cancer activity and method for the treatment of cancer
WO2002020023A1 (en) * 2000-09-01 2002-03-14 Oxycal Laboratories, Inc. Methods and compositions for potentiating cancer chemotherapeutic agents
US6468980B1 (en) * 2000-09-01 2002-10-22 Oxycal Laboratories, Inc. Methods and compositions for potentiating cancer chemotherapeutic agents

Also Published As

Publication number Publication date
EP0249632A1 (en) 1987-12-23
AU6846687A (en) 1987-06-30
EP0249632A4 (en) 1988-06-20

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