Effects of treatments with alpha-difluoromethylornithine and hyperthermia on the growth and polyamine metabolism of Harding-Passey murine melanoma

Abstract

The oral administration of alpha-difluoromethylornithine (DFMO), an enzyme-activated inhibitor of ornithine decarboxylase (ODC), produced a marked decrease in the rate of growth of amelanotic Harding-Passey melanoma transplanted in mice. The half-life of this compound in Harding-Pasey melanoma was 30 min. A combined treatment of DFMO and hyperthermia did not show any synergistic effect on the inhibition of tumor growth, and no differences in the levels of tumor ODC, S-Adenosylmethionine decarboxylase (SAMDC) and polyamines were observed between single and combination treatments. DFMO-treatment alone produced a decrease of about 80% in spermidine concentration in melanoma, while in other tissues such as kidney, the diminution of spermidine was only moderate. ODC activity was reduced greatly in the kidney and moderately in melanoma. However, the activity of SAMDC increased up to 30-fold in DFMO-treated melanoma, while only a moderate increase was observed in the renal enzyme. Melanoma tyrosinase activity did not increase with the treatment with DFMO. These results indicate that the inhibition of amelanotic Harding-Passey melanoma growth by DFMO is not caused by the stimulation of cell differentiation, and that in this system polyamine depletion caused by this drug does not produce an enhancement in the heat-induced cytotoxicity.