RESISTANCE TO 9-BETA-D-ARABINOFURANOSYLADENINE IN CULTURED LEUKEMIA L 1210 CELLS

  • 1 January 1983
    • journal article
    • research article
    • Vol. 43  (10) , 4791-4798
Abstract
A cultured line of L1210 [mouse] leukemia cells, designated L1210/ara-A, was selected for resistance to 9-.beta.-D-arabinofuranosyladenine (ara-A) by a series of 72 h exposures to increasing concentrations of ara-A in the presence of 1 .mu.M deoxycoformycin. Cells of the resistant line were .apprx. 1/10 as sensitive as were cells of the parent line to the effects of ara-A on proliferation, viability and tumorigenicity. Cross-resistance, as determined by comparison of drug effects on rates of proliferation of L1210/C2 and L1210/ara-A cells, was seen with adenosine, deoxyadenosine, methylmercaptopurine ribonucleoside, tubercidin and cordycepin, but not with 1-.beta.-D-arabinofuranosylcytosine or with 9-.beta.-D-arabinofuranosyl-2-fluoroadenine. The levels of resistance to methylmercaptopurine ribonucleoside, cordycepin and tubercidin were considerably greater than that seen with ara-A itself. L1210/C2 and L1210/ara-A cells were compared with respect to the effects of ara-A on cell size distributions, DNA distributions, labeling indices and apparent rates of DNA synthesis, and the differences seen were consistent with inhibition of DNA synthesis and unbalanced growth as the major mechanism of ara-A cytotoxicity. The decreased sensitivity of DNA synthesis in L1210/ara-A cells treated with ara-A, relative to L1210/C2 cells, was due to reduced intracellular accumulation of ara-A phosphates in the resistant line. Phosphorylation of ara-A, adenosine and tubercidin, but not deoxyadenosine or deoxycytidine, was greatly reduced in intact L1210/ara-A cells, relative to L1210/C2 cells, and adenosine kinase activity in extracts of L1210/ara-A cells was negligible. Resistance to ara-A and cross-resistance to tubercidin, methylmercaptopurine ribonucleoside and cordycepin are attributed to loss of adenosine kinase activity.