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Inhibition of DNA repair in cells treated with a combination of alkylating agents

O S Frankfurt1, D Seckinger, E V Sugarbaker

  • 1Oncology Laboratory, Cedars Medical Center, Miami, Florida 33136.

Anticancer Research
|July 1, 1993
PubMed

Insights

DNA repair inhibitors aphidicolin (AP) and hydroxyurea (HU) enhance chemotherapy effectiveness in ovarian cancer cells. Combining these inhibitors with certain chemotherapy drugs, like L-phenylalanine mustard (L-PAM), significantly increases cancer cell killing.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • DNA repair mechanisms are crucial for cellular survival and can influence cancer chemotherapy efficacy.
  • Ovarian carcinoma cells exhibit varying sensitivities to DNA-damaging agents and possess repair pathways that can lead to drug resistance.

Purpose of the Study:

  • To investigate the impact of DNA repair inhibitors, aphidicolin (AP) and hydroxyurea (HU), on the cytotoxicity of chemotherapy agents in human ovarian carcinoma cells.
  • To determine if inhibiting DNA repair can overcome drug resistance and enhance the effectiveness of combined chemotherapies.

Main Methods:

  • Human ovarian carcinoma cell lines (A2780 and cisplatin-resistant A2780/CP) were treated with various combinations of chemotherapy drugs (L-phenylalanine mustard, cisplatin, thioTEPA) and DNA repair inhibitors (AP, HU).
  • Cytotoxicity was assessed, and the effects on DNA repair inhibition were evaluated.
  • The role of protein synthesis inhibition was examined using cycloheximide.

Main Results:

  • Aphidicolin (AP) or hydroxyurea (HU) significantly enhanced the cytotoxicity of combined chemotherapy regimens (L-PAM + cisplatin, cisplatin + thioTEPA) in A2780 cells.
  • AP + HU post-treatment inhibited DNA repair and enhanced cell killing when cells were treated with L-PAM alone.
  • In cisplatin-resistant cells (A2780/CP), AP + HU enhanced L-PAM cytotoxicity but not cisplatin; however, DNA repair inhibitors decreased cisplatin IC90 when combined with L-PAM or thioTEPA.

Conclusions:

  • Inhibiting DNA repair with AP or HU can potentiate the cytotoxic effects of certain chemotherapy combinations in ovarian cancer.
  • This strategy shows promise in overcoming drug resistance, particularly when combining alkylating agents, suggesting a potential therapeutic approach to improve ovarian cancer treatment outcomes.

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