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.

Keywords:

• Thiarabine
• in vivo resistance
• ara-C
• P388 leukemia

ACKNOWLEDGMENTS

This work was supported by NCI grants P01-CA34200 and R01-CA124952. The authors gratefully acknowledge the technical assistance of the staff of the Cancer Therapeutics and Immunology Department. J. Tubbs and G. Jones assisted with data management, and K. Cornelius prepared the manuscript.

Disclosure: The use of thiarabine was patented by Southern Research Institute, which receives licensing fees and royalty payments from the commercial development and use of this agent. Southern Research Institute does distribute some of this money to Drs. Secrist, Parker, and Waud.

Notes

^aThe untreated median lifespan for P388/0 was 11.0, 10.0, 10.0, and 11.0 days for expt. nos. 1, 2, 3, and 4, respectively.

^bNet log₁₀ reduction in the tumor cell population between the beginning and the end of therapy, based on the median day of death of mice that died or were euthanized.

^cThe untreated median lifespan for P388/T-araC was 12.0, 11.0, 11.5, and 12.5 days for expt. nos. 1, 2, 3, and 4, respectively.

^aThe untreated median lifespan for P388/0 was 11.0, 10.0, 10.0, and 11.0 days for expt. nos. 1, 2, 3, and 4, respectively.

^bNet log₁₀ reduction in the tumor cell population between the beginning and the end of therapy, based on the median day of death of mice that died or were euthanized.

^cThe untreated median lifespan for P388/T-araC was 12.0, 11.0, 11.5, and 12.5 days for expt. nos. 1, 2, 3, and 4, respectively.

^aThe untreated median lifespan for P388/0 was 11.0, 10.0, 10.0, and 11.0 days for expt. nos. 1, 2, 3, and 4, respectively.

^bNet log₁₀ reduction in the tumor cell population between the beginning and the end of therapy, based on the median day of death of mice that died or were euthanized.

^cThe untreated median lifespan for P388/T-araC was 12.0, 11.0, 11.5, and 12.5 days for expt. nos. 1, 2, 3, and 4, respectively.

^anmoles/mg protein/minute for dCMP deaminase and pmoles/mg protein/minute for dCyd kinase and dCyd deaminase.

^bMean ± SD.

^cn = 6.

^dNumber in parentheses is percent of P388/0 value.

^en = 2.