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Expression of p53 in Cisplatin-resistant Ovarian Cancer Cell Lines: Modulation with the Novel Platinum Analogue (1R, 2R-Diaminocyclohexane)(trans-diacetato)(dichloro)-platinum(IV)¹

Departments of Gynecologic Oncology [G. S. H.], Molecular Oncology [G. B. M.], and Clinical Investigation [A. R. K., R. C. B., Z. H. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The compound (1R,2R-diaminocyclohexane)(trans-diacetato)(dichloro)platinum(IV) (DACH-acetato-Pt) is a novel platinum-based antitumor agent with clinical potential against cisplatin-resistant disease that is under development in our laboratory. In view of the central role of the wild-type p53 tumor suppressor gene in drug-induced apoptosis, we evaluated the cytotoxicity of cisplatin and DACH-acetato-Pt in a panel of cisplatin-resistant ovarian tumor models with differing p53 status. Cisplatin was relatively more effective against mutant or null p53 cell lines (continuous drug exposure IC₅₀, 1.2–3.3 µM) than it was against those harboring wild-type p53 (IC₅₀, 2.8–9.9 µM). In contrast, DACH-acetato-Pt was considerably more active in wild-type p53 models (IC₅₀, 0.17–1.5 µM) than it was in mutant or null models (IC₅₀, 2.7–11.3 µM). Inactivation of wild-type p53 function in OVCA-429 cells by the human papillomavirus type 16 (HPV 16) E6 plasmid increased resistance to DACH-acetato-Pt by 3–5-fold, which confirmed the drug’s dependence on wild-type p53 for its high cytotoxic potency. Differences between the two platinum agents were also evident in cell cycle studies: cisplatin arrested both wild-type and mutant p53 cells in G₂-M, whereas DACH-acetato-Pt arrested wild-type p53 cells in G₁ and mutant p53 cells in G₂-M. The G₁ arrest by DACH-acetato-Pt was abrogated in HPV 16 E6 transfectant clones of OVCA-429 cells. In agreement with effects on cell cycle progression, a 2-h pulse exposure to low concentrations (25 µM) of DACH-acetato-Pt induced marked increases in p53 and p21^Waf1/Cip1 expression in OVCA-429 cells. Cisplatin, in direct contrast, had no effect on expression of p53 or p21^Waf1/Cip1 until the drug concentration was increased to 125 µM. In HPV 16 E6 transfectants of OVCA-429 cells, induction of p53 by the two agents was severely attenuated, and corresponding increases in p21^Waf1/Cip1 were abrogated. This suggests that p21^Waf1/Cip1 increases were p53 dependent. Collectively, the results demonstrate that DACH-acetato-Pt is very distinct from cisplatin. In particular, the greater activity of DACH-acetato-Pt in cisplatin-resistant wild-type p53 ovarian tumor models can be ascribed to its ability to more efficiently induce p53 protein and activate p53 functions.

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