Anticancer research
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Anticancer research · May 1994
Substituted 2-acylpyridine-alpha-(N)-hetarylhydrazones as inhibitors of ribonucleotide reductase activity and L1210 cell growth.
A series of substituted 2-acylpyridine-alpha-(N)-hetarylhydrazones was prepared and studied for their effects on mammalian ribonucleotide reductase activity using a highly purified enzyme preparation from Ehrlich tumor cells and on mouse leukemia L1210 cell growth in culture. Pyridine-2-aldehyde-2-pyridylhydrazone (PH 22), ethyl-2-pyridylketone-I-phthalazinylhydrazone (PH 22-25) and pyridine-2-aldehyde-2'-quinolylhydrazone (PQ 22) inhibited purified ribonucleotide reductase activity and inhibited L1210 cell growth in culture. ⋯ There was no effect on RNA synthesis. These data indicate that these substituted hydrazones are potent inhibitors of tumor cell growth through the inhibition of ribonucleotide reductase.
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Anticancer research · May 1994
The role of glutathione (GSH) in determining sensitivity to platinum drugs in vivo in platinum-sensitive and -resistant murine leukaemia and plasmacytoma and human ovarian carcinoma xenografts.
Numerous studies performed in vitro have suggested a role for glutathione (GSH) in determining the sensitivity/resistance of tumour cells to various platinum-based drugs. Few studies have extended these findings into the in vivo setting. We have measured GSH levels in two murine (ADJ/PC6 plasmacytoma and L1210 leukaemia and their acquired platinum-drug-resistant sublines) and five human ovarian carcinoma (PXN/100, PXN/109T/C, SKOV3, HX/62 and OVCAR-3) tumour models of varying sensitivity to cisplatin. ⋯ However, in other tumours (e.g., the acquired cisplatin resistant ADJ/PC6 plasmacytoma) non-GSH mediated mechanisms of resistance (such as enhanced DNA repair) probably account for the resistance. Pretreatment of animals with oral buthionine sulfoximine (BSO), which resulted in approximately 70% depletion in tumour GSH levels, failed to potentiate the antitumour efficacy of either cisplatin (using the ADJ/PC6 and L1210 models) or the 1,2-diaminocyclohexane (DACH) platinum-drug, tetraplatin (using the ADJ/PC6 model). These BSO plus or minus cisplatin data suggest a limited role for such combinations in the clinic.