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In vivo characterization of P388 leukemia resistant to mitomycin C
W C Rose1, J B Huftalen, W T Bradner
1Experimental Therapeutics Dept., Bristol-Myers Research Center, Wallingford, CT 06492.
Abstract:
A line of P388 leukemia resistant to mitomycin C (MMC) was successfully developed in vivo by treating mice bearing parental P388 (P388/0) with MMC followed by serial passage of the surviving leukemic cells. From this P388/MMC line, a subline was derived by not treating the passage mice with MMC (P388/MMC-NP); resistance to MMC was stable for as many as 56 weeks of transplantation. The chemosensitivities of each P388 line to assorted anticancer drugs were compared in vivo. Both P388/MMC and P388/MMC-NP had similar patterns of drug cross-resistance and collateral sensitivity. With respect to alkylating agents (e.g. cyclophosphamide, Platinol and chlorambucil), there was generally a partial degree of cross-resistance, sometimes only detectable at suboptimal dose levels. With respect to DNA binders or intercalators (e.g. actinomycin D, luzopeptin A, amsacrine, doxorubicin), the extent of cross-resistance varied from none (dihydoxyanthraquinone) to marked (doxorubicin). Antimitotic inhibitors (vinblastine and vincristine) were completely cross-resistant, as were some miscellaneous natural agents (rebeccamycin, VP-16, sesbanimide, and elsamicin, a chartreusin analog). Antimetabolites (e.g. methotrexate and 6-thioguanine) showed no cross-resistance and even demonstrated some occasional evidence of collateral effectiveness.
Insights
Researchers developed mitomycin C-resistant P388 leukemia in vivo. This resistant cell line exhibited cross-resistance to various anticancer drugs, with varying sensitivity patterns observed for different drug classes.
Area of Science:
- Pharmacology
- Cancer Research
- Drug Resistance
Background:
- Developing drug-resistant cancer cell lines is crucial for understanding treatment failure.
- Mitomycin C (MMC) is an alkylating agent used in chemotherapy.
- P388 leukemia is a common model for studying anticancer drug efficacy.
Purpose of the Study:
- To develop a mitomycin C-resistant P388 leukemia cell line in vivo.
- To compare the chemosensitivity profiles of the resistant and parental cell lines.
- To investigate patterns of drug cross-resistance and collateral sensitivity.
Main Methods:
- In vivo development of mitomycin C-resistant P388 leukemia (P388/MMC) through serial passage.
- Derivation of a subline (P388/MMC-NP) without continuous drug exposure.
- In vivo chemosensitivity testing of P388/MMC and P388/MMC-NP against various anticancer agents.
Main Results:
- Stable mitomycin C resistance was maintained in P388/MMC and P388/MMC-NP lines.
- Similar cross-resistance patterns were observed between the two lines.
- Varying degrees of cross-resistance were noted for alkylating agents and DNA binders.
- Complete cross-resistance was seen with antimitotic inhibitors and some natural agents.
- Antimetabolites showed no cross-resistance, with some evidence of collateral effectiveness.
Conclusions:
- The developed P388/MMC line provides a model for studying acquired resistance mechanisms.
- Cross-resistance patterns are drug class-dependent, offering insights into drug selection.
- Understanding these resistance mechanisms can inform future therapeutic strategies.