Add time:07/15/2019         Source:sciencedirect.com

The relative rates at which normal and malignant cells oxidize 4-hydroxycyclophosphamide/aldophosphamide to carboxyphosphamide, a reaction catalyzed by NAD-linked aldehyde dehydrogenases and by aldehyde oxidase, may be potentially important in determining the relative sensitivities of these cells to cyclophosphamide. Potential inhibitors of the NAD-linked aldehyde dehydrogenase catalyzed reaction were sought in the present investigation. Pretreatment with cyanamide markedly depressed (70–98 percent) the catalytic activity of NAD-linked aldehyde dehydrogenases present in the 105,000 g soluble fraction and the solubilized 105,000 g particulate fraction of rat and mouse liver and kidney, and of W256 ascites carcinosarcoma cells, when butyraldehyde was used as the substrate. Disulfiram, diethyldithiocarbamic acid or allyl alcohol pretreatment was relatively ineffective. Acrolein or cyclophosphamide pretreatment was without effect. Oxidation of 4-hydroxycyclophosphamide/aldophosphamide to carboxyphosphamide by hepatic soluble and solubilized particulate fractions under incubation conditions optimal for the expression of NAD-linked aldehyde dehydrogenase activity was virtually abolished when the subcellular fractions were obtained from rats or mice treated with cyanamide. Conversion of 4-hydroxycyclophosphamide/aldophosphamide to carboxyphosphamide in vivo was markedly depressed in cyanamide-treated. functionally anephric, mice. Cyanamide should prove to be a useful tool in ascertaining whether the rate of 4-hydroxycyclophosphamide/aldophosphamide oxidation to carboxyphosphamide is an important determinant in the sensitivity of normal and malignant cells to cyclophosphamide.

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