Development of a mitoxantrone-resistant P 388 in vivo: approaches to overcome resistance.
A normally, relatively sensitive P 388 developed resistance within few passages (P 388/Mitox) by in vivo treatment with suboptimal doses (1 mg/kg i.v.) of mitoxantrone. This resistance remained stable over 50 generations without further drug treatment. Immunization with irradiated cells (30 Gy) 7 days before tumor challenge led to partial rejection, proving that there was a higher immunogenicity of the resistant line in comparison to the parenteral P 388 line. The P 388/Mitox showed cross-resistance towards doxorubicin, daunorubicin and vincristine. Cis-DDP and bleomycin had in the resistant line significantly better antineoplastic efficacy than in the source P 388 and should be taken into consideration as second-line therapy following development of clinical mitoxantrone resistance. Nifedipine, a calcium channel blocker, and the immunosuppressive agent ciclosporin A were able to overcome resistance partially, but the mechanisms are still unclear. The P 388/Mitox can be considered as an interesting in vivo model for further research concerning resistance mechanisms and reversal of resistance.
Academy of Sciences of GDR, Department of Clinical and Experimental Chemotherapy, Berlin-Buch.
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Fichtner
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Becker
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Lemm
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Winterfeld
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D004351:Drug Resistance; D007941:Leukemia P388 / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D008942:Mitoxantrone / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001761:Bleomycin; D008942:Mitoxantrone; D002945:Cisplatin