5,10,-methylene-tetrahydrofolate as a modulator of a chemotherapeutic agent

• US 5,534,519 A
• Filed: 10/20/1994
• Issued: 07/09/1996
• Est. Priority Date: 05/11/1990
• Status: Expired due to Term

• Current Assignee: University of Southern California
• Original Assignee: University of Southern California
• Inventors: Gustavsson, Bengt G., Spears, Colin P.
• Primary Examiner(s): Criares, Theodore J.
• Application Number:
  US08/326,414
• Time in Patent Office: 628 Days
• Field of Search: 514/274
• US Class Current: 514/274
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim

Abstract

The present invention relates to the compound 5,10-methylene-tetrahydrofolate (CH₂ FH₄), and its solution product isomer FH₄, therapeutic uses of these compounds, and compositions thereof. CH₂ FH₄ and FH₄ strongly modulate the in vivo antitumor effects of 5-Fluorouracil.

Claims

1. A composition for inhibiting TS activity in mammalian cells comprising an amount of unnatural diastereomer (6S)-CH₂ FH₄ or unnatural diastereomer (6R)-FH₄ sufficient to effect said activity inhibition, together with a pharmaceutically acceptable carrier.

2. The composition of claim 1, further comprising an additional active agent selected from the group consisting of 5-fluoracil and compounds which are metabolized to fluorodeoxyuridylate (FdUMP).

3. The composition of claim 2 wherein the compound which is metabolized to FdUMP is fluoridine, ftorafur, or 5'"'"'-deoxyfluorouridine.

4. The composition of claim 1 further comprising an agent that stabilizes CH₂ FH₄ or FH₄.

5. The composition of claim 4 wherein the agent that stabilizes CH₂ FH₄ or FH₄ is an ascorbate salt.

6. The composition of claim 4 wherein the agent that stabilizes CH₂ FH₄ or FH₄ is reduced glutathione.

7. The composition of claim 1 further comprising formaldehyde.

8. A method of inhibiting TS activity in mammalian cells comprising administering to said cells an amount of unnatural diastereomer (6S)-CH₂ FH₄ or unnatural diastereomer (6R)-FH₄ sufficient to effect said activity inhibition.

9. The method of claim 8 wherein said unnatural diastereomer (6S)-CH₂ FH₄ or unnatural diastereomer (6R)-FH₄ is administered in a dosage of 5-500 mg/m².

10. The method of claim 9 wherein said unnatural diastereomer (6S)-CH₂ FH₄ or unnatural diastereomer (6R)-FH₄ is administered in a dosage of 20-200 mg/m².

11. The method of claim 8 wherein said method comprises administering natural diastereomer (6S)-FH₄ and said unnatural diastereomer (6R)-FH₄ together in a ratio of from 1:

20 to 20;

1 and wherein said sum of said diastereomers is 5-500 mg/m².

12. The method of claim 8, further comprising administering an additional active agent selected from the group consisting of 5-fluoracil and compounds which are metabolized to fluorodeoxyuridylate (FdUMP).