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Modulation of target enzyme associated with the action of antifolates

Y M Rustum1, S Cao, M B Yin

  • 1Grace Cancer Drug Center and Experimental Therapeutics, Roswell Park Cancer Institute, Buffalo, NY 14263.

Advances in Enzyme Regulation
|January 1, 1994
PubMed

Insights

The antifolate drug ICI-D1694 inhibits human ileocecal carcinoma growth by targeting thymidylate synthase. Its effects, including DNA breaks, are reversed by thymidine and leucovorin.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Antifolate drugs are crucial in cancer therapy.
  • Thymidylate synthase (TS) is a key enzyme in DNA synthesis and a target for antifolates.
  • Understanding drug mechanisms is vital for optimizing cancer treatment.

Purpose of the Study:

  • To evaluate the cytotoxicity of the antifolate thymidylate synthase inhibitor ICI-D1694 against human ileocecal carcinoma.
  • To investigate the molecular effects and reversal mechanisms of ICI-D1694.

Main Methods:

  • Cell culture of human ileocecal carcinoma.
  • Drug exposure assays to determine IC50 values.
  • Analysis of DNA single-strand breaks.
  • Reversal studies using thymidine and leucovorin.

Main Results:

  • ICI-D1694 demonstrated potent inhibition of cell growth with IC50 values of 73 nM (2 hr) and 3 nM (72 hr).
  • The drug induced time-dependent DNA single-strand breaks after maximal thymidylate synthase inhibition.
  • Drug effects were reversible by thymidine and leucovorin (> 1 microM).
  • Leucovorin competed with ICI-D1694 at the cell membrane level, while thymidine competed at the thymidylate synthase level.

Conclusions:

  • ICI-D1694 is a potent inhibitor of human ileocecal carcinoma growth.
  • The drug's mechanism involves thymidylate synthase inhibition and DNA damage.
  • Reversal by thymidine and leucovorin highlights distinct mechanisms of action and potential combination strategies.

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