Inhibitory effect of some esters of 4-hydroxy-5-nitro-4,5-dihydrothymine on the growth of tumor cells.

New analogs of 4-hydroxy-5-nitro-4,5-dihydrothymine, namely 4-acyloxy-5-nitro-4,5-dihydrothymines (where: acyl = acetyl, benzoyl, mono- and dichloroacetyl) were synthesized and tested for their toxicologic and antitumor effects on Ehrlich ascites tumor cells and Ehrlich solid tumor. Best results were found for the mono- and dichloroacetyl derivatives.

Release from the Crabtree effect by hypoxic cell radiosensitizers.

The Crabtree effect can be observed when the O2 consumption of tumour cells or of mammalian cells grown in culture is measured in physiological medium containing glucose. The effect of 2 hypoxic cell radiosensitizers, misonidazole and NDPP, on the O2 consumption of Ehrlich ascites tumour cells was compared in media with and without glucose. A stimulatory effect on O2 consumption was found for 5--20mM misonidazole as well as for 0.5mM NDPP, both in media containing 10(-2)M glucose. Thus glucose induced a Crabtree effect in Ehrlich tumour cells, expressed as 38--45% inhibition of O2 consumption relative to that in the same medium without glucose. The stimulatory effect of misonidazole and NDPP on O2 utilization in medium with glucose undoubtedly appeared as a release from the Crabtree effect.

Characterization of metronidazole-phosphate, a water-soluble metronidazole derivative, as a radiosensitizer of hypoxic cells.

A water-soluble derivative of metronidazole (Flagyl) was synthetized with the purpose to overcome some practical difficulties in the clinical administration of the drug. The derivative, a phosphate ester of metronidazole, was characterized for different physical-chemical properties. It had a low toxicity both in vitro and in vivo. In vitro, it retained a radiosensitizing effect specific for hypoxic cells which was, however, decreased in comparison with the parent compound. The decreased sensitization was related to a decreased one-electron reduction potential and octanol/water partition coefficient. In mice, metronidazole-phosphate had a prolonged blood life in comparison to metronidazole.

Effect of anoxic radiosensitizers on cellular and mitochondrial oxygen consumption and respiration control ratio.

Misonidazole increased oxygen consumption of Ehrlich ascites cells and reversed the blockage of oxidative phosphorylation induced by amytal and KCN. It alos increased oxygen consumption of mitochondria in the presence of alpha-ketoglutarate substrate, but decreased the respiratory control ratio. Cellular oxygen consumption decreased, but mitochondrial consumption was increased by metronidazole, and the respiratory control ratio was not affected by this substance. It was concluded that misonidazole influences respiration in a similar way to uncouplers, and the interaction site for both substances is at the NADH level. These respiratory effects can be of importance in altering radiation response in multicellular tissues.

The levels of NAD and NADH in blood of patients with cancer.

The levels of nicotinamide adenine dinucleotide (NAD) and NADH in blood of patients with cancer in various stages of development as well as their modification after glucose administration were determined in 188 respectively 77 cases. NAD was significantly decreased in patients with cervix and breast carcinoma but unaltered in patients with metastatic cancers (and lung carcinoma) comparatively with healthy subjects. At 48 hours after i.v. administration of glucose, NAD increased significantly in patients with cervix carcinoma but was unaltered in patients with metastatic cancers (an lung carcinoma). NADH in both cases has given little conclusive results.