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.
Fichtner
I
I
Academy of Sciences of GDR, Department of Clinical and Experimental Chemotherapy, Berlin-Buch.
Becker
M
M
Lemm
M
M
Winterfeld
G
G
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