Collateral sensitivity to cross-linking agents exhibited by cultured L1210 cells resistant to oxazaphosphorines

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.