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Synergistic interactions between UCN-01 and various anticancer agents in vitro: Relationship to p53 function

  1. Author:
    Monks, A.
    Vaigro-Wolff, A.
    Hose, C.
    Sausville, E. A.
    O'Connor, P. M.
    1. Year of Conference: 1997
  2. Conference Name: Annual Meeting of the American Association for Cancer Research
    1. 38
    2. Pages: A2157
  4. Type of Work: Meeting Abstract
  1. Abstract:

    UCN-01 has recently been shown to be a potent abrogator of G2 checkpoint function in cells with disrupted p53 function. Based on this premise, we evaluated the interaction between UCN-01 and 9 antitumor drugs, in 2 breast cancer cell lines. As anticipated, MDA-MB-435 (mutant p53) showed strong, significant synergy with the combination of UCN-01 and the DNA cross linking agents cisplatin, thiotepa, melphalan and mitomycin C. Two topoisomerase II inhibitors, Adriamycin and etoposide showed only weak to moderate synergy with UCN-01, but topotecan, an inhibitor of topoisomerase I, resulted in a strong synergistic interaction. In contrast, MCF-7 (normal p53 function) exhibited no synergy with these drug combinations. Microtubule inhibitors taxol and vincristine were additive with UCN-01 in all cell lines tested. These results support the premise that the synergy observed can be related to checkpoint function and p53 status. However, studies with the lung cancer cell line H23 (mutant p53) showed no synergy with UCN-01 and the DNA damaging agents. This suggests the possibility that either the G2 checkpoint target of UCN-01 is defective in H23, or factors in addition to p53 status may influence the drug interactions with UCN-01. We are continuing to investigate the mechanism underlying this effect, which may be important in designing initial clinical trials of UCN-01.

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