Date on Master's Thesis/Doctoral Dissertation

8-2011

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Committee Chair

States, J. Christopher

Author's Keywords

Ovarian cancer; Hyperthermic; Cisplatin; HIPEC; Arsenic; Pseudo-G1

Subject

Cisplatin; Ovaries--Cancer

Abstract

Epithelial Ovarian cancer (EOC) is the leading cause of gynecological cancer death in the USA. Recurrence rates are high after front-line platinum chemotherapy and most patients eventually die from platinum-resistant disease. P53 plays an important role in cellular response to platinum-DNA damage. It transcriptionally activates XPC, a platinum-DNA damage recognition protein in the global genome repair (GGR), sub-pathway of nucleotide excision repair (NER). The goal of this research is to investigate the effect of a novel combination of cisplatin, sodium arsenite (NaAs02) and hyperthermia (CPA 39 DC) on EOC cells with different p53 status. Human EOC cells were treated with cisplatin ± 20 IJM NaAs02 for 1 h at 37 or 39°C. NaAs02 ± hyperthermia selectively sensitized wild-type p53 EOC cells to cisplatin by suppressing XPC and enhancing cellular and DNA platinum accumulation. In contrast, only hyperthermia sensitized p53-mutated and p53-null EOC cells to cisplatin by enhancing cellular and DNA platinum accumulation. Cisplatin ± NaAs02 at 37 or 39°C induced pseudo-G1 associated apoptosis in p53 expressing cells. Co-treatment with HSP90 inhibitor 17-DMAG plus CPA 39°C greatly sensitized EOC cells by enhancing cellular platinum accumulation. In order to translate the in vitro findings in an in vivo model, metastatic ovarian cancer was established in nude mice by intraperitoneal injection of A2780/CP70 human EOC cells. Tumor bearing mice were perfused with 3 mg/kg body weight (BW) cisplatin ± 26 mg/kg BW NaAs02 for 1 h at 37 or 43°C using a murine intraperitoneal chemotherapy system developed in our laboratory. Cisplatin induced NER proteins XPC and XPA and suppressed mismatch repair protein MSH2 that is associated with resistance. However, co-treatment with NaAs02 at 37 or 43°C suppressed XPC, restored higher levels of MSH2 and enhanced tumor platinum uptake. Platinum and arsenic generally accumulated in systemic tissues during intraperitoneal lavage and decreased 24 h after perfusion. In conclusion, CPA 39 °C alone or combined with 17-DMAG has the potential to sensitize EOC to cisplatin by attenuating NER, activating mismatch repair, enhancing tumor platinum accumulation and activating apoptotic cell death.

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