alanosine and Melanoma

We conducted parallel phase II trials of cimetidine as a single agent and the combination N-phosphonacetyl-L-aspartate (PALA) plus L-alanosine among 40 previously untreated patients with biopsy-proven, measurable disseminated malignant melanoma. We did not design the trial to be a comparative assessment of the two regimens. Among 19 patients treated with cimetidine, 300 mg orally four times daily, there was one complete response of extensive pleural and pulmonary metastases for 16+ months and two partial regressions of soft tissue lesions for 7 and 21+ months, respectively. Among 21 patients treated with the combination regimen, there was only one partial response in soft tissue for 1 month. The median times to progression and death were 1.4 and 6 months, respectively, for cimetidine, and 1.3 and 4 months, respectively, from the combination of PALA plus L-alanosine. Among patients who progressed on initial treatment, there were no responses in 12 who received crossover therapy with cimetidine and 11 with the combination regimen. Two patients treated with the combination program had severe stomatitis, two developed renal failure, and one had severe leukopenia and thrombocytopenia. Recognizing the limitations of small sample size, these early observations suggest that cimetidine may have intriguing implications in the management of disseminated malignant melanoma.

Topics: Alanine; Antineoplastic Combined Chemotherapy Protocols; Aspartic Acid; Cimetidine; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Melanoma; Middle Aged; Phosphonoacetic Acid; Pleural Neoplasms; Soft Tissue Neoplasms

A human melanoma cell line (MM96L) had a spontaneous mutation rate at the HGPRT locus of approx. 7 times normal. The cells had elevated dATP and dGTP pools, lacked purine nucleoside phosphorylase (PNP) and were sensitive to killing by deoxyadenosine, deoxyinosine and related purines but not to inosine or hypoxanthine. Four other melanoma cell lines exhibited a range of nucleoside sensitivities and dNTP pool sizes. Failure of intact MM96L cells to degrade exogenous deoxyadenosine and deoxyinosine to hypoxanthine was confirmed by NMR of culture medium. Normal melanocytes were PNP+ and were insensitive to deoxyinosine. Comparison of the metabolites of [14C]deoxyinosine from MM96L and a PNP+ cell line of similar doubling time (HeLa) showed that both cell types produced 14C-labelled guanine and adenine nucleotides, with [14C]dATP and [14C]dADP being found in MM96L. This indicates that human sAMP synthetase or a similar enzyme catalyses the conversion of dIMP to dAMP, the resultant elevation of dATP causing base misincorporation and a mutator phenotype.

Topics: Alanine; Antibiotics, Antineoplastic; Antineoplastic Agents; Cell Survival; Chromatography, High Pressure Liquid; Deoxyadenosines; Deoxyribonucleotides; HeLa Cells; Humans; Hypoxanthine Phosphoribosyltransferase; Inosine; Magnetic Resonance Spectroscopy; Melanoma; Mutation; Ribavirin; Thioguanine; Tumor Cells, Cultured

The authors conducted a phase II study of L-alanosine in 39 patients (19 without prior chemotherapy) in advanced malignant melanoma. The intravenous dose was 250 mg/m2/days 1-3 repeated at 3-week intervals. There were two objective regressions (5%) in conjunction with generally transient and tolerable hematologic and gastrointestinal toxicity. L-alanosine as used in our study has limited activity against malignant melanoma.

Topics: Alanine; Antibiotics, Antineoplastic; Drug Evaluation; Female; Humans; Male; Melanoma; Middle Aged; Neoplasm Metastasis; Skin Neoplasms