Treatment of chemotherapeutic agent and antiviral agent toxicity with acylated pyrimidine nucleosides

Abstract

The subject invention discloses compounds, compositions and methods for treatment and prevention of toxicity due to chemotherapeutic agents and antiviral agents. Disclosed are acylated derivatives of non-methylated pyrimidine nucleosides. These compounds are capable of attenuating damage to the hematopoietic system in animals receiving antiviral or antineoplastic chemotherapy.

Description

[0001] This application is a continuation in part of copending U.S. application Ser. No. 08 / 176,485, filed Dec. 30, 1993, which is a continuation in part of copending U.S. application Ser. No. 08 / 061,381, filed May 14, 1993, which is a continuation in part of copending U.S. application Ser. No. 903,107, filed Jun. 25, 1992, which is a continuation-in-part application of copending U.S. application Ser. No. 724,340, filed Jul. 5, 1991, which is a continuation-in-part of U.S. application Ser. No. 438,493, filed Jun. 27, 1989, which is a continuation-in-part of U.S. application Ser. No. 115,929, filed Oct. 27, 1987, and Ser. No. 724,340 is a continuation-in-part application of copending U.S. application Ser. No. 487,984, filed Feb. 5, 1990, which is a continuation-in-part of U.S. application Ser. No. 115,923 filed Oct. 27, 1987. All of these applications are hereby incorporated by reference.[0002] This invention relates generally to treatment of chemotherapeutic agent and antiviral agen...

AI Technical Summary

Benefits of technology

[0023] It is a primary object of this invention to provide a method for effectively preventing or treating toxic symptoms of antiviral or anticancer chemotherapy, including but not limited to damage to the hematopoietic system and to gastrointestinal mucosa.

[0026] A further object of the invention is to provide a method for preventing or ameliorating gastrointestinal epithelium damage due to cytotoxic chemotherapy agents.

[0027] These and other objects of the invention are achieved by oral or parenteral administration of acylated derivatives of non-methylated pyrimidine nucleosides, e.g. acylated derivatives of uridine, deoxyuridine, cytidine, or deoxycytidine, which are administered to animals, including mammals such as humans. The administration of these compounds alone, or in combination, is useful in preventing or ameliorating toxic effects of cytoreductive chemotherapy in animals.

Problems solved by technology

A major complication of cancer chemotherapy and of antiviral chemotherapy is damage to bone marrow cells or suppression of their function.

Specifically, chemotherapy damages or destroys hematopoietic precursor cells, primarily found in the bone marrow and spleen, impairing the production of new blood cells (granulocytes, lymphocytes, erythrocytes, monocytes, platelets, etc.).

Chemotherapeutic agents can also result in subnormal formation of platelets which produces a propensity toward hemorrhage.

Inhibition of erythrocyte production can result in anemia.

The clinical utility of 5-FU is limited by its toxicity (especially to bone marrow).

Specifically, its clinical utility is limited by a low therapeutic ratio (the ratio of toxic dose to effective dose; a high therapeutic ratio implies that a drug has efficacy with little toxicity).

Stomatitis (ulceration of mucosa in the mouth), is particularly troublesome to patients, making eating and swallowing painful.

Clinical trials involving the administration of uridine have been complicated due to the biological properties of uridine itself.

Consequently, parenteral administration of uridine is necessary for clinically significant reversal of 5-FU toxicity, which requires use of a central venous catheter, since phlebitis has been a problem in early clinical trials when uridine was administered via a small intravenous catheter (van Groeningen et al.

Further, there is considerable discomfort and inconvenience to the patients.

The liver, however, has relatively high levels of the enzyme dihydropyrimidine dehydrogenase, which degrades 5FU, producing metabolites which are not useful in cancer chemotherapy and which furthermore contribute to 5-FU toxicity.

Other pyridimines, including uridine, thymidine, thymine, and cytosine are either less effective than uracil or no better in potentiating the antitumor efficacy of FT without unacceptably potentiating toxicity.

They noted that despite the fact that pyrimidines and pyrimidine nucleosides, at doses which are inactive alone, markedly potentiate the antileukemic effects of small doses of FUDR or FU, it has not been possible with any combination to improve significantly and with any degree of regularity the results which can be obtained with maximum tolerated doses of FU or FUDR alone.

Although deoxyuridine, by inhibiting the catabolism of the fluoropyrimdines permitted adminstration of lower doses, deoxyuridine there was no improvement in antitumor activity at equitoxic doses of the combination versus FU or FUDR alone.

As in the case of uridine, problems of poor bioavailability after oral administration limit the clinical utility of administration of deoxycytidine, cytidine, and deoxyuridine themselves for modulation of toxicity of chemotherapy agents.

Side effects of PALA primarily involve damage to gastrointestinal toxicity and mucositis.

AZT prolongs the lifespan of patients infected with HIV, but also impairs hematopoiesis, producing leukopenia and anemia.

The methods disclosed in the prior art cited above for administering these pyrimidine nucleosides to modify chemotherapy in the clinical setting are neither practical (prolonged infusion of deoxycytidine or uridine via a central venous catheter requires hospitalization, risk of infection, and discomfort to the patient) or satisfactory (orally administered uridine is poorly absorbed; therapeutically adequate doses of oral uridine produce diarrhea).

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