Median Effect and Long Term Recovery Analysis of Biological Modifier Interactions With Difluoromethylornithine on the Proliferation of Human Melanoma Cells

Abstract

The ability of difluoromethylornithine (DFMO), a specific polyamine synthesis inhibitor, to interact with various biological modifiers to inhibit the colony‐forming growth of human melanoma cells was determined by using the median effect principle to computer model the strength of two agent interactions. Either alpha‐ or gamma‐IFN (interferon) in combination with DFMO resulted in a synergistic inhibition on human melanoma colony formation. For human melanoma cells which were not resistant to 13‐cis RA (retinoic acid), an additive suppression on colony formation was obtained with the retinoid‐DFMO combination. Dexamethasone (DEX) interacted with DFMO to yield a synergistic reduction in melanoma colony number on glucocorticoid sensitive cells and no growth enhancement with DFMO on glucocorticoid resistant melanoma lines. Human melanoma cells displayed differential long‐term growth sensitivity to DFMO treatment. C8146C human melanoma cells were terminally growth‐inhibited by a 96 h exposure to DFMO, in a manner which was concentration and time dependent. The proliferation of C82‐7A melanoma cells was inhibited by 95% in presence of DFMO, but upon removal of DFMO the cells regained their ability to proliferate and form colonies. The simultaneous addition of DEX plus alpha‐IFN plus 13‐cis‐RA with DFMO caused most of the human melanoma cells in these lines to become permanently growth arrested. Pre‐treatment with DEX plus alpha‐IFN plus 13‐cis RA, but without DFMO, did not have any long term effect on the ability of melanoma cells to recover and proliferate in soft agar. Since human melanoma cells are heterogeneous with respect to sensitivity to these hormones, it may be advantageous to use DFMO with several of these agents in combination.

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials

“…DFMO in combination with interferon-γ treatment causes growth arrest in human melanoma cell lines. 120 No clinical or epidemiologic studies of the effects of DFMO on melanoma in humans have been reported. A randomized, double-blinded, placebo-controlled phase 3 trial for the prevention of KC in patients with a history of the disease randomized 291 participants to receive either oral DFMO (500 mg/m 2 daily) or placebo.…”

“…ODC and polyamine production are induced by UV exposure in the skin 119 , and both oral and topical administration of DFMO reduce the number of KC tumors in UV-induced mouse models. DFMO in combination with interferon gamma treatment causes growth arrest in human melanoma cell lines 120 .…”