Isolation and Characterization of a Murine P388 Leukemia Line Resistant to Thiarabine

Abstract

A murine P388 leukemia line fully resistant to thiarabine was obtained after five courses of intraperitoneal treatment (daily for nine consecutive days). The subline was sensitive as was the parental P388/0 line to 5-fluorouracil, gemcitabine, cyclophosphamide, cisplatin, melphalan, BCNU, mitomycin C, doxorubicin, mitoxantrone, etoposide, irinotecan, vincristine, and paclitaxel, but was cross resistant (at least marginally) to three antimetabolites: palmO-ara-C, fludarabine phosphate, and methotrexate. The deoxycytidine kinase activity in the subline was comparable to that for P388/0, whereas the dCMP deaminase activity was 43% of that for P388/0. No deoxycytidine deaminase activity was detected in either of the leukemias. There appeared to be little, if any, difference in the metabolism of deoxycytidine, cytidine, or thiarabine in the two leukemias.

Lack of in vivo cross-resistance with 4′-thio-ara-C against drug-resistant murine P388 and L1210 leukemias

“…Studies in our laboratories have shown that P388/VP-16 leukemia (selected for resistance in vivo) does not overexpress the mdr -1 gene, which is probably a reflection of the fact that the line was selected for resistance in vivo. The line does exhibit decreased DNA topoisomerase II activity in comparison to the parental line [13]. Even though the mechanisms of paclitaxel resistance operative in P388/PTX leukemia have not been investigated, studies conducted with other tumor cell lines have revealed the resistance to be multifactorial – overexpression of the mdr -1 gene, molecular changes in the target molecule (β-tubulin), changes in apoptotic regulatory and mitosis checkpoint proteins, and changes in lipid composition and potentially the overexpression of interleukin 6 [14].…”