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Effect of Steroids and Fluoropyrimidines on Lymphomas

II. In Vivo Studies on Tumor Resistance and Collateral Sensitivity^*

Julia McCain Lampkin-Hibbard, Kanai L. Mukherjee and Charles Heidelberger

( Cancer Research Laboratory, University of Miami, Coral Gables, Florida; and McArdle Memorial Laboratory, The Medical School, The University of Wisconsin, Madison, Wisconsin)

Biochemical studies have been carried out in vivo in mice bearing tumors both sensitive and resistant to 9--fluorohydrocortisone (9-AFH) in the same host, to determine the mechanism of resistance to steroids and of collateral sensitivity to 5-fluorouracil (FU). The mechanism of collateral sensitivity was probably due to the incorporation of FU-2-C¹⁴ into RNA to an extent 2.7 times greater in the P1798 lymphoma resistant to 9-AFH (sensitive to FU) than in the P1798 sensitive to 9-AFH. Further evidence in support of this mechanism of collateral sensitivity to FU was provided by a twofold greater incorporation of uracil-2-C¹⁴ into the RNA uracil of the untreated, control, resistant tumors (sensitive to FU) than into the RNA uracil of the untreated tumors (sensitive to 9-AFH). The percentage of nucleotides in the acid-soluble extract of the resistant tumors (sensitive to FU) was the same as that of the sensitive tumors (sensitive to 9-AFH) following administration of FU-2-C¹⁴.

Studies on the mechanism of resistance to 9-AFH showed that 9-AFH inhibited the incorporation of formate-C¹⁴ into DNA thymine to a greater (2.5 times) extent in the tumors sensitive to 9-AFH than in those resistant to it.

The combination of 9-AFH + FU, each at a dosage of 15 mg/kg, was more effective at inhibiting the incorporation of uracil-2-C¹⁴ into the acid-soluble uracil compounds in the sensitive and resistant tumors in the same mouse than was either drug alone, and the combination produced complete regression of both tumor lines.

9-AFH inhibited the incorporation of uracil-2-C¹⁴ into RNA uracil in the tumors sensitive to the steroid but not in the tumors resistant to it. FU inhibited the incorporation of uracil-2-C¹⁴ into RNA uracil in the tumors resistant to 9-AFH (sensitive to FU) but not in the tumors sensitive to 9-AFH. In mice bearing both sensitive and resistant tumors, 9-AFH at a dose of 25 mg. per kg. caused regression of established tumors sensitive to steroid but not of the resistant tumors; conversely, FU caused regression of the tumors resistant to the steroid but not of the tumors sensitive to it.

^* Supported by P.H.S. 3.63588 and Contract SA-43-ph-3040 from the Cancer Chemotherapy National Service Center, National Cancer Institute, National Institutes of Health, Public Health Service, to the University of Miami; and Grant C-2832, National Cancer Institute, National Institutes of Health, Public Health Service, to the University of Wisconsin.

American Cancer Society Professor of Oncology.

Received 10/ 1/62.