Establishment of l1210 leukemia cells resistant to the distamycin-a derivative (FCE 24517): Characterization and cross-resistance studies
✍ Scribed by Cristina Geroni; Enrico Pesenti; Giovanna Tagliabue; Dario Ballinari; Nicola Mongelli; Massimo Broggini; Eugenio Erba; Maurizio D'Incalci; Federico Spreafico; Maria Grandi
- Publisher
- John Wiley and Sons
- Year
- 1993
- Tongue
- French
- Weight
- 723 KB
- Volume
- 53
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
N-deformyl-N-~4-N,N-bis(2-chloroethylam~no)benzoyl] distamycin-A (FCE 24517) is a new cytotoxic anti-tumor agent in phase-I clinical trials. We have isolated stable FCE-245 17resistant cell sublines from murine leukemia LIZ10 cells by in vitro exposure to the drug. FCE 245 I 7 selects a mixed population of resistant cells: the L I 2 I0/245 17, cell line in vitro was in fact resistant to the selecting agent (RI 48.3), as well as to L-PAM (RI 5.4) and DX (RI 8.6) and over-expressed the mdr-I gene. When L1210/24517, cells were implanted in vivo and evaluated for sensitivity to the same agents, resistance was observed only to FCE 24517 and partially to L-PAM. whereas DX had the same anti-tumor efficacy as on the sensitive line. The clone derived from the above subline (LI 2 I0/245 I 72) was resistant to FCE 245 17, distamycin-A and other cytotoxic compounds bearing the distamycin-A skeleton, and fully sensitive to DX and other anti-tumor compounds involved in the multi-drug resistance mechanisms, with a complete disappearance of the mdr phenotype. L1210/245172 cell line is partially cross-resistant to L-PAM, this resistance being accounted for by higher GSH intracellular levels, which however do not influence the resistance to FCE 24517. In fact, BSO treatment was capable of significantly modifying only the cytotoxicity of L-PAM. Our data suggest that L1210/245172 cells present a mechanism of resistance specific for FCE 24517 and related molecules.