Characterization of a novel mouse reticular cell sarcoma M5076 subline resistant to cisplatin

Abstract

A novel murine tumor resistant to cis‐diamminedichloroplatinum (cisplatin, DDP) was obtained (M5/DDP) after 22 passages in which mice bearing the ovarian reticular cell sarcoma M5076 (M5) were treated with DDP. Although DDP conserved some inhibitory activity on growth of M5/DDP, it was much less effective than on M5. Treatment with DDP did not prolong the survival time of mice with M5/DDP, whereas it markedly prolonged survival of M5‐bearing mice. MS and M5/DDP tumors shared many biological and biochemical features. They were similar histologically, they metastasized reproducibly to the liver and were poorly immunogenic. Their growth rates were comparable; their DNA index, percentage of cells in S phase and intra‐cellular glutathione content were also similar. In both tumors, DDP caused an accumulation of cells in S late‐G₂‐M within 24 hr after drug treatment. However, this was efficiently reversed in M5/DDP, whereas it worsened and persisted longer in M5. Cross‐resistance was observed between DDP and its analogues carboplatin and iproplatin, but tetraplatin retained marginal activity on M5/DDP tumor. Several alkylating agents tested [L‐phenylalanine mustard (L‐PAM); cyclophosphamide (CTX); chlorambucil (CLB); 1,3‐bis(2‐chloroethyl)‐I‐nitrosourea (BCNU) and dacarbazine (DTIC)] were not totally cross‐resistant to DDP, but showed greater activity on M5 than on M5/DDP. Other non‐alkylating anti‐neoplastic drugs showed a similar degree of activity on M5 and M5/DDP. 5‐Aza‐2′‐deoxycytidine (Aza‐d‐Cyd) was very effective on both tumors, etoposide (VP‐16) and cytosine arabinoside (Ara‐C) had no activity and Adriamycin (ADR) was weakly effective.