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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. 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.
Insights
A novel murine tumor model resistant to cisplatin (DDP) was developed. This cisplatin-resistant tumor (M5/DDP) showed cross-resistance to analogues but retained sensitivity to other agents, offering insights into platinum-based chemotherapy resistance.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Cisplatin (DDP) is a cornerstone platinum-based chemotherapy agent.
- Acquired resistance to DDP limits its clinical efficacy in various cancers, including ovarian sarcoma.
- Understanding the mechanisms of DDP resistance is crucial for developing effective treatment strategies.
Purpose of the Study:
- To develop and characterize a novel murine tumor model resistant to cis-diamminedichloroplatinum (cisplatin, DDP).
- To investigate the cross-resistance patterns of the DDP-resistant M5/DDP tumor model with DDP analogues and other chemotherapeutic agents.
- To compare the biological and biochemical features of the parental M5 tumor and the DDP-resistant M5/DDP tumor.
Main Methods:
- Development of a DDP-resistant murine ovarian reticular cell sarcoma M5076 (M5) tumor model (M5/DDP) through serial in vivo DDP treatment.
- Evaluation of DDP efficacy on tumor growth and survival in M5 and M5/DDP bearing mice.
- Assessment of cross-resistance to DDP analogues (carboplatin, iproplatin, tetraplatin) and various alkylating and non-alkylating agents.
- Comparative analysis of histological features, metastatic patterns, immunogenicity, growth rates, DNA index, S-phase fraction, and intracellular glutathione content between M5 and M5/DDP tumors.
Main Results:
- The M5/DDP tumor model exhibited significant resistance to DDP compared to the parental M5 tumor, with DDP failing to prolong survival in M5/DDP-bearing mice.
- M5 and M5/DDP tumors shared similarities in histology, liver metastasis, low immunogenicity, growth rate, DNA index, S-phase percentage, and glutathione content.
- DDP induced S-G2-M cell cycle arrest in both tumors, but this effect was transient in M5/DDP and persistent in M5.
- Cross-resistance was observed with carboplatin and iproplatin, while tetraplatin showed marginal activity. Several alkylating agents were less effective against M5/DDP than M5. Non-alkylating agents like 5-Aza-2'-deoxycytidine showed similar activity against both tumors.
Conclusions:
- The developed M5/DDP murine tumor model effectively recapitulates DDP resistance observed in clinical settings.
- The distinct cellular response to DDP-induced cell cycle arrest in M5/DDP suggests altered drug sensitivity mechanisms.
- The differential sensitivity to various chemotherapeutic agents highlights potential alternative treatment options for DDP-resistant ovarian sarcomas.