Title:  Drug combinations containing AZT

United States Patent:  6,365,578

Assignee:  Roger Williams General Hospital (Providence, RI)

Filed:  July 6, 1993

Combinations of 3'-azido-3'-deoxythymidine (AZT) with 5-fluorouracil (FUra) or its precursor 5-fluoro-2'-deoxyuridine (FUDR) or methoxtrexate (MTX) exhibit increased cytotoxicity and increased therapeutic index in treatment of carcinomas.

Description of the Invention

This invention relates to the treatment of mammals suffering from carcinomas, and, more particularly, those suffering from human colon adenocarcinoma, and pertains more specifically to treatment to inhibit or prevent metastasis of the malignancy and/or to induce regression of tumors by the administration of medication consisting essentially of 3'-azido-3'-deoxythymidine or a pharmacologically acceptable salt thereof (AZT) as one component, in combination with a second component which is any of 5-fluorouracil (FUra) or 5-fluoro-2'-deoxyuridine (FUDR) or methotrexate (MTX).

Human colon cancer is the second most common malignancy in the United States and, when metastatic, has been an incurable disease. Chemotherapy based upon 5-fluorouracil (FUra) or its corresponding pro-drug 5-fluoro-2'-deoxyuridine (FUDR) has been the treatment of choice for the disease in its advanced stages, but objective responses have been observed only in a minority of patients, with the great majority of them lasting only a few months, as reported by Arbuck, Cancer, Volume 63, 1036-1044 (1989). However, both FUra and FUDR are highly toxic drugs with narrow margins of safety. MTX is also highly toxic.

It has now been found that treatment of carcinomas, with medication including both the AZT component and the second component defined above is more effective than treatment with either component alone. Not only does the combination of both components inhibit the growth of human colon tumor cells to a much greater extent than either component alone, but this is accomplished without significant increase in toxicity to the mammal as a whole, assessed by determination of mortality, changes in body weight, and changes in white blood cell counts. While applicants do not wish to be bound by a theory of operation of the combination of drug components, it is believed that the second component enhances the cytotoxicity and tissue-specificity of the AZT component, resulting both in increased effectiveness and an increased therapeutic index of the combination.

In practicing the invention, both components of the medication may be mixed together and administered simultaneously, either by intravenous or intra-arterial injection or orally where possible in any conventional carrier or vehicle such as normal saline or 5% aqueous dextrose solution, or in any other non-toxic pharmacologically acceptable vehicle or carrier. Alternatively, each component may be administered separately provided they are spaced apart by no more than about 48 hours, preferably by less than about 6 hours. In general, the less time elapsing between administration of the two components the better. In the case of separate administration, the sequence in which the components are administered is not critical, either component being administered first, although it is generally preferred that the AZT component be administered last. In the case of FUra and FUDR, administration, as is well known, is preferably by intravenous or intra-arterial injection, whereas AZT and MTX may be administered orally or by intravenous or intra-arterial injection. Each of the components may be used in any of its generally available forms, and each may be administered by any conventional procedure. However, when administered separately, the AZT component is preferably in injectable form and the second component such as FUra, can be administered by injection, e.g., intravenous or intra-arterial.

The relative proportions of the two components may be varied over a wide range from about 1 to 10 parts by weight of the AZT component, preferably from 5 to 8 parts, for each part of the second component.

The dosage may also vary over a wide range, the upper limit being generally determined by the toxicity of the second component. The toxicity of all of the components when used individually has long been known and is not greatly changed by using both components together. However, while the standard dose of AZT has been 0.4 to 0.6 g/m² /day according to the prior art, the minimum dose of AZT for humans in the present invention is 3 g/m² /day, preferably 6-9 g/m² /day or even more. In the preferred embodiment of the invention the second component is 5-fluorouracil (FUra) or its prodrug 5-fluoro-2'-deoxyuridine (FUDR) which is catabolized in vivo to FUra. In the case of FUra the dose for humans in the present invention is preferably 0.4-1 g/m² /day with a total not exceeding 1 g/m² per course of therapy regardless of the number of days over which it is spread. At least one week must be allowed as a rest period, preferably two weeks, between courses of therapy. The dose of FUDR is preferably 0.8-1 g/m² / day for humans, and the dose of methotrexate for humans in the present invention about 0.05-0.2 g/m² /day.

Claim 1 of 6 Claims

What is claimed is:

1. A method of treating a mammal suffering from carcinoma to inhibit growth of said carcinoma which comprises administering to said mammal effective doses of 3'-azido-3'-deoxythymidine and methotrexate, wherein said 3'-azido-3'-deoxythymidine and said methotrexate are administered within a 48 hour time period, and are more effective than the combined effects of separate administration of 3'-azido-3'-deoxythymidine and methotrexate.

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