The long-term objective is to define the molecular relationship between acquired resistance to teniposide (VM-26) and pleiotropic drug resistance (PDR). The association of two chromosomes with homogeneously staining regions (HSRs) in VM-26-resistant L1210 sublines (L1210/VM-26) and of cross-resistance to etoposide (VP-16), vincristine dactinomycin (DACT), and adriamycin (ADRIA) provides a model for studying the relationship at the gene level between acquired resistance to VM-26 and PDR. The objective will be accomplished with the techniques of molecular cloning. The approach will be: (1) to demonstrate the presence of similar amplified gene sequences in the genoic DNA and the HSRs; (2) to compare levels in L1210 cells and L1210/VM-26 cells of the mRNA transcribed from the gene that conveys resistance to VM-26; (3) to translate the mRNA for resistance and compare the product with two novel proteins in L1210/VM-26 cells; (4) to correlate the copy-number of the amplified gene with resistance to VM-26; and (5) to examine the similarities of PDR as expressed with acquired resistance to VCR, DACT, or VM-26 by mouse cells and human cells. These studies are expected to show that a unique amplified gene, possibly two, in the genomic DNA and the HSRs relates to VM-26 resistance and that larger amounts of mRNA for the gene are present in L1210/VM-26 cells than in L1210 cells. If the product of this mRNA and either of the 2 novel proteins in L1210/VM-26 cells is similar, then a phenotypic expression will have been related to VM-26 resistance and, hopefully, to PDR. Studies with these drug-resistant cell lines will indicate the source of the variation expressed in PDR, that is acquired with resistance to different drugs, as well as the nature of differences between species. Drug resistance, which in reference to patients is more correctly named drug refractoriness, limits chemotherapy in more than 50% of the cases. In many instances, the cancers of patients become resistant to the same drugs that elicit PDR in laboratory models. The proposed investigation is expected to relate PDR with gene amplification, and more importantly to provide the necessary preparation for future studies in which PDR can be definitively demonstrated to limit chemotherapy clinically.
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| Roberts, D; Meyers, M B; Biedler, J L et al. (1989) Association of sorcin with drug resistance in L1210 cells. Cancer Chemother Pharmacol 23:19-25 |
| Roberts, D W; Foglesong, P D; Parganas, E et al. (1989) Reduced formation of lesions in the DNA of a multidrug-resistant L1210 subline selected for teniposide resistance. Cancer Chemother Pharmacol 23:161-8 |
