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Collateral Sensitivity to Cross-Linking Agents Exhibited by Cultured L1210 Cells Resistant to Oxazaphosphorines¹

Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

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.

¹ Supported by USPHS Grant CA 21737. A description of parts of this investigation appears in a dissertation submitted by J. E. Low in 1983 to the Department of Pharmacology, University of Minnesota, Minneapolis, in partial fulfillment of the requirements for the Ph.D. degree (25).

² To whom requests for reprints should be addressed, at the University of Minnesota, Department of Pharmacology, 3-260 Millard Hall, 435 Delaware ST. S.E., Minneapolis, MN 55455.

³ Present address: Mayo Clinic, Rochester, Minnesota 55901.

Received 5/25/84. Accepted 11/ 6/84.