Drug Resistance in Multiple Myeloma Associated With High In Vitro Incorporation of 3H-Thymidine

Abstract

AbstractIn multiple myeloma, tumor cell mass and labeling index correlate with subsequent survival duration, but do not predict for response to treatment. In the present study we have autoradiographically measured the incorporation of 3H-thymidine as determined by the number of grains over the myeloma nuclei in bone marrow aspiration samples. In 33/37 patients with <50% tumor regression or progressive disease, the pretreatment grain count was $$20/myeloma nucleus. Conversely, values of < 20 were found in 27/29 patients who had $$50% cell mass reduction. Survival duration was significantly better (p < 0.001) in patients with grain counts <20. Sixty percent of the patients with both a low labeling index ($$3%) and grain count (<20) were alive at 48 mo, whereas 15/17 patients with a high labeling index and grain count had a median survival of <6 mo. In a subset of 22 patients, there was a significant correlation between in vitro resistance to melphalan, adriamycin, and vincristine as tested in the myeloma stem cell colony assay system and a grain count of >20. We can only speculate as to the reasons for the increased 3H-thymidine uptake by myeloma cells resistant to treatment, however, it could be associated with accumulation of excess DNA and/or increased unscheduled DNA synthesis following injury from alkylating agents.