alanosine and acivicin

The effects of three different nucleotide biosynthesis inhibitors were tested on differentiation and purine/pyrimidine metabolism in HL60 cells. On the three nucleotide biosynthesis inhibitors, acivicin and mycophenolic acid were able to differentiate HL60 cells, while alanosine failed to do so. Differentiation of HL60 cells by acivicin and mycophenolic acid was associated with substantial decreases in both the guanylate and adenylate pools and appeared to be dependent on the state of depletion of intracellular GTP. Simultaneous addition of guanosine or guanine to mycophenolic acid-treated cells restored the GTP pool and prevented differentiation from occurring. Adenine or adenosine had no such effect, while hypoxanthine and inosine partially reversed the differentiation. In acivicin-treated cells, simultaneous addition of guanine caused partial prevention of differentiation. Even though treatment of HL60 cells with alanosine resulted in the depletion of guanylates, this effect was secondary to the depletion of adenylates and developed only upon prolonged exposure. In all the inhibitor-treated cells the activities of the key regulatory enzymes of de novo purine biosynthesis were affected. Even though the measurable activity of hypoxanthine/guanine phosphoribosyl transferase was enhanced in inhibitor-treated cells, the activity of the salvage pathway was inhibited in mycophenolic acid and alanosine-treated cells. Besides de novo purine nucleotide biosynthesis, de novo pyrimidine nucleotide biosynthesis was also inhibited in inhibitor-treated cells. The inhibition of purine and pyrimidine nucleotide biosynthesis in mycophenolic acid, acivicin and alanosine-treated cells resulted in an increase in the steady-state concentration of PRPP. Since purine and pyrimidine nucleotides play an important role in the synthesis of important macromolecules, it can be suggested that depletion of guanine ribonucleotide as a result of inhibition of early de novo purine biosynthesis, or due to specific inhibition of de novo guanine nucleotide biosynthesis, may be an obligatory step in the initiation of differentiation in mycophenolic acid and acivicin-treated HL60 cells.

Topics: Alanine; Cell Differentiation; Cell Division; Formates; Hematopoiesis; Humans; Hypoxanthine; Hypoxanthines; In Vitro Techniques; Inosine Monophosphate; Isoxazoles; Leukemia, Myeloid; Mycophenolic Acid; Phosphoribosyl Pyrophosphate; Purines; Pyrimidines; Reactive Oxygen Species; Tumor Cells, Cultured

One hundred and forty-four evaluable patients with recurrent or metastatic renal cell carcinoma (RCC) were treated with vinblastine infusion (n = 35), L-alanosine (n = 36), acivicin (n = 27), or aminothiadiazole (n = 46). Observed objective response rates of 9%, 3%, 4%, and 2%, respectively indicate that noe of these agents has significant antineoplastic activity in recurrent or metastatic RCC. Multivariate analysis of survival data suggests that initial performance status, time from initial diagnosis to study entry, and the presence or absence of lung metastases are important prognostic factors for survival. After adjustment for these factors, treatment assignment was also seen to be of prognostic value. All four treatments were generally well tolerated. There were no reports of life-threatening or lethal toxicities; however, 37% of the patients experienced severe reactions to treatment, primarily myelosuppression, anemia, neuropathies, and mucositis.

Topics: Adult; Aged; Alanine; Antineoplastic Agents; Carcinoma, Renal Cell; Drug Administration Schedule; Drug Evaluation; Female; Humans; Isoxazoles; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Neoplasm Recurrence, Local; Oxazoles; Thiadiazoles; Vinblastine