Exth-57. Interaction of 4-demethyl-4-cholesteryloxycarbonylpenclomedine (dm-choc-pen) With Melanoma Melanin Metabolism and Cell Death
Year: 2016
Type: conference-abstract
Abstract: 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. 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 DM- CHOC-PEN and monitored daily until death or moribund and sacrificed. Temozolamide (TMZ) was used as control. 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 DM- CHOC-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 N7- 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.
Source: Neuro-Oncology
Language: English
Subfield: Toxicology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2588120845