The John Jackson Award for Best Clinical Presentation

Marcus Ware, MD, PhD (Tulane-Ochsner) Interaction of 4-Demethyl-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) with Melanoma Melanin Metabolism and Cell Death Andrew Conger, MD (LSUHSC-NO) Pineoblastoma in Adults Rimal Hanif, MD (LSUHSC-S) The Kurdistan Experience: Building Neurosurgical Capacity in a Medically Underdeveloped Region Scientific Session I Moderator: Dr. Bharat Guthikonda Interaction of 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) with Melanoma Melanin Metabolism and Cell Death L.R. Morgan, E. Benes, A.H. Rodgers, DEKK-TEC, Inc.; B.S. Jursic, University of New Orleans, New Orleans, LA; R.F. Struck, Cancermedica LLC, W.R. Waud, Southern Research Institute, Birmingham, AL; P. Friedlander, Mount Sinai School of Medicine, New York, NY; R.S. Weiner, Tulane University Health Sciences Center, Marcus Ware, Ochsner Hospital, New Orleans, LA Purpose: DM-CHOC-PEN is a polychlorinated pyridine cholesteryl carbonate, which is in Phase I clinical trials in patients with advanced cancer. B-16 melanoma was evaluated in vitro and in vivo for sensitivity to DM-CHOC-PEN. Methods: B-16 melanoma cells were cultured and drugs were added to the cells in a growth phase and after 16 hrs removed. Adult C57BL mice in groups of 5-6 female mice with measurable SC growing B-16 melanoma nodules were dosed IP daily (150-200 mg/kg) for 5 days with DMCHOC-PEN and monitored daily until death or moribund and sacrificed. Temozolamide (TMZ) was used as control. Results: In vitro, DM-CHOC-PEN had an IC50 of 0.5 μg/mL vs. B-16 melanoma cells. Floating heavily melanotic cells that formed were separated and analyzed for DM-CHOC-PEN and found to contain 125% more drug than did adhered amelanotic cells. For the in vivo studies, T-C for mice bearing B-16 melanoma treated with DM-CHOC-PEN vs. controls was 60-142%; thus supporting the in vitro observations. For TMZ, the T-C was 78%. Electronic modeling studies support DMCHOC-PEN’s ability to act as a pyridinium co-factor in the transfer of electrons from DOPA to the intermediary metabolism pool. Previously, we reported that dacarbazine inhibited DOPA oxidase and melanin formation in melanoma pts. Although tyrosine-DOPA transport/metabolism is not a target for DM-CHOC-PEN (its MOA is considered to be via alkylation/adduct formation with N 7 guanine), the accumulation of intracellular melanin does influence/interfere with cellular metabolism. Given this finding, there is a possible role of DOPA oxidase in drug selection to treat melanoma. Supported by NCI/SBIR grants – CA85021 and CA132257. Marcus Ware, MD, PhD (Tulane-Ochsner)