asta-z-7557 and Leukemia-P388

The sensitivity of cultured L1210 and P388 cells, sensitive (L1210/0, P388/0) and resistant (L1210/CPA, P388/CPA) to cyclophosphamide in vivo, to five oxazaphosphorine and eight nonoxazaphosphorine cross-linking agents was determined. Each of the resistant sublines was cross-resistant to all of the oxazaphosphorines tested. The P388/CPA cell line was also cross-resistant to all of the nonoxazaphosphorines but, in most cases, not nearly to the same extent. The L1210/CPA cell line was collaterally sensitive to all but one of the nonoxazaphosphorines, in which case it was equisensitive. Changes in sensitivity could not be accounted for by changes in intracellular pH values, or by changes in intracellular inorganic phosphate or acid-soluble organic phosphate concentrations. Inasmuch as the L1210/CPA cell line was specifically resistant to the oxazaphosphorines, identification of the phenotypic basis for this resistance should serve to identify a potentially important determinant with regard to the basis for the oncotoxic specificity of this group of agents.

Topics: Animals; Cross-Linking Reagents; Cyclophosphamide; Drug Resistance; Hydrogen-Ion Concentration; Leukemia L1210; Leukemia P388; Mice; Phosphates

The sensitivity of cultured L1210 and P388 cells sensitive (L1210/0, P388/0) and resistant (L1210/OAP, P388/CLA) to oxazaphosphorines, to 4-hydroperoxycyclophosphamide, ASTA Z-7557, phosphoramide mustard, and acrolein was determined in the absence and presence of known (disulfiram, diethyldithiocarbamate, cyanamide) or suspected [ethylphenyl(2-formylethyl)phosphinate] inhibitors of aldehyde dehydrogenase activity. The L1210/OAP cell line is resistant specifically to the oxazaphosphorines; P388/CLA cells are partially cross-resistant to other cross-linking agents. All four inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of the oxazaphosphorines, 4-hydroperoxycyclophosphamide and ASTA Z-7557, against L1210/OAP and P388/CLA cells; in the presence of a sufficient amount of inhibitor, sensitivity was essentially fully restored in both cases. The inhibitors did not potentiate the cytotoxic action of the nonoxazaphosphorines, phosphoramide mustard and acrolein, against these cell lines. The cytotoxic action of the oxazaphosphorines and nonoxazaphosphorines against L1210/0 and P388/0 cells was not potentiated by any of the aldehyde dehydrogenase inhibitors. Inhibitors of xanthine oxidase or aldehyde oxidase activities did not potentiate the cytotoxic action of the oxazaphosphorines against L1210/OAP cells. These observations strongly suggest that (a) aldehyde dehydrogenase activity is an important determinant with regard to the sensitivity of a cell population to the oxazaphosphorines; (b) L1210/0 and P388/0 cells lack the relevant aldehyde dehydrogenase activity; (c) the phenotypic basis for the resistance to oxazaphosphorines by L1210/OAP cells is aldehyde dehydrogenase activity; and (d) the major reason that P388/CLA cells are resistant to oxazaphosphorines is aldehyde dehydrogenase activity.

Topics: Aldehyde Dehydrogenase; Animals; Cell Line; Cross-Linking Reagents; Cyanamide; Cyclophosphamide; Disulfiram; Drug Resistance; Leukemia L1210; Leukemia P388; Leukemia, Experimental; Mice