The purpose of this project is to continue to design, synthesize, and test peptide antagonists of LHRH antagonists which have very low histamine releasing properties (equivalent to LHRH, or less) and with respect to gonadotropin suppression, are ten-fold more potent than currently available LHRH antagonists. GRANTS=R01CA57499 Advanced squamous cell carcinoma of the heal and neck has shown a 14-30% response rate to cisplatin as a single agent and 40-70% response rate to cisplatin + 5-FU. However, the responses to cisplatin and other chemotherapeutic agents are usually of short duration. Ormaplatin (NSC 363812) has demonstrated activity against cisplatin-resistant tumors in preclinical studies. Therefore, we plan to evaluate the activity of ormaplatin in recurrent or locally progressive head and neck cancer. The drug will be administered as a single 30 min infusion every 4 weeks at the dosage determined in the ongoing phase I studies. Patients will be evaluated from both toxicity an objective tumor response. We also plan to perform detailed pharmacokinetic and biotransformation studies in conjunction with this phase II study. We plan to obtain the t1/2beta for PtCI2(dach), identify and determine pharmacokinetic parameters for other active biotransformation products, and determine pharmacokinetic parameters for the inactive biotransformation products. Finally, there has been considerable interest in using levels of Pt-DNA adducts as a prognostic indicator of tumor response, but the theoretical basis for this assay is currently uncertain. We have hypothesized that Pt-DNA adduct levels in peripheral leukocytes are determined by the AUC for active platinum species in the circulation and have proposed experiments to test that hypothesis. It has been hypothesized that Pt-DNA adducts in peripheral leukocytes are reflective of Pt-DNA adduct levels in tumor tissue, but this has not been directly tested. We plan to determine Pt- DNA adduct levels in those patients with accessible tumor an correlate it with Pt-DNA adduct levels in their peripheral leukocytes. We have hypothesized that adduct levels should be predictive of toxicity. Thus, we plan to correlate Pt-DNA adduct levels in peripheral leukocytes with parameters of toxicity. Finally, we have hypothesized that total cellular Pt in peripheral leukocytes should correlate with toxicity and/or tumor response and have proposed to determine both total cellular Pt and Pt-DNA adducts in peripheral leukocytes from this patient population and to correlate these two parameters with each other and with toxicity and efficacy. These studies should significantly advance our understanding of platinum pharmacokinetics, improve the usefulness of platinum determinations in peripheral leukocytes as prognostic indicators of toxicity or efficacy, and could potentially introduce a more active agent in the treatment of recurrent had and neck cancer.
