Characterization of a novel mouse reticular cell sarcoma M5076 subline resistant to cisplatin.
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. M5 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-phenyalanine mustard (L-PAM); cyclophosphamide (CTX); chlorambucil (CLB); 1,3-bis(2-chloroethyl)-1-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.
Ferrari
A
A
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Damia
G
G
Erba
E
E
Rossi
C
C
Mandelli
R
R
D'Incalci
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors; D002460:Cell Line; D002945:Cisplatin / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D005260:Female; D005434:Flow Cytometry; D005978:Glutathione / Q000032:analysis; D016403:Lymphoma, Large B-Cell, Diffuse / Q000032:analysis / Q000188:drug therapy* / Q000401:mortality; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000032:analysis / Q000188:drug therapy* / Q000401:mortality; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D005978:Glutathione; D002945:Cisplatin