Genetic analysis of chemoresistance in primary murine lymphomas.
Understanding the basis of chemoresistance is a principal goal of molecular oncology. We have exploited a murine lymphoma model and retroviral gene transfer to rapidly generate a series of spontaneous tumors differing only in a gene of interest, and subsequently studied the impact of the test gene on the treatment sensitivity of tumors at their natural site. We demonstrate that the Bcl-2 oncoprotein produces multi-drug resistance when assessed in primary lymphomas in vivo. In contrast, this effect was dramatically reduced when the primary lymphomas were subjected to long-term culture, and completely missed in the standard clonogenic survival assay. This model highlights the importance of physiological test systems to address the complexity of clinical drug resistance and provides a novel strategy to evaluate compounds targeting specific genetic lesions.
Schmitt
C A
CA
Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
Rosenthal
C T
CT
Lowe
S W
SW
D000220:Adaptation, Biological; D000818:Animals; D002999:Clone Cells; D046508:Culture Techniques / Q000379:methods; D018432:Drug Resistance, Multiple / Q000235:genetics*; D018014:Gene Transfer Techniques; D019254:Genes, bcl-2; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D012190:Retroviridae / Q000235:genetics; D014407:Tumor Cells, Cultured
D016271:Proto-Oncogene Proteins c-myc