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Cytogenetic and Molecular Characterization of Tumors in Nude Mice Derived from a Multidrug-resistant Human Leukemia Cell Line¹

Department of Radiation Oncology, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724 [A. B. H., J. M. T.], and Department of Biochemical and Clinical Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38101 [W. T. B.]

We have evaluated whether selection of a human tumor leukemic line for resistance to vinblastine (Velban; VLB) alters its tumorigenicity. To address this question, CEM and CEM/VLB₁₀₀ cells [which express the multiple drug-resistant (MDR) phenotype via amplification of the P-glycoprotein gene] were characterized by several techniques including chromosome banding, in situ hybridization, Southern blotting, RNA dot blotting, in vitro drug sensitivity, and tumorigenicity in nude mice. Analysis of the chromosome banding patterns of both drug-sensitive CEM cells and the MDR CEM/VLB₁₀₀ cells revealed that the two lines differed primarily by the presence of a large metacentric marker chromosome associated with the acquisition of VLB resistance. In situ hybridization of a P-glycoprotein complementary DNA to metaphase chromosomes showed that the amplified P-glycoprotein genes in the CEM/VLB₁₀₀ cell line were localized to this large marker. Tumorigenicity of both the CEM and CEM/VLB₁₀₀ cell lines was measured after injection of 10⁷ cells/nude mouse. The results showed that 4 of 4 drug-sensitive and 4 of 5 drug-resistant cell lines formed tumors in 5–10 wk. By comparison with the parental line, three of the four tumors arising from the CEM/VLB₁₀₀ line retained their drug-resistance properties as measured by vinblastine resistance in vitro and elevated P-glycoprotein mRNA expression associated with P-glycoprotein gene amplification. In addition, tumors retaining the MDR phenotype also retained the large metacentric marker chromosome. One tumor arising from CEM/VLB₁₀₀ reverted to the drug-sensitive phenotype, with a resultant decrease in P-glycoprotein mRNA expression and loss of P-glycoprotein gene amplification. This revertant was also missing the large metacentric marker present in all cells from the CEM/VLB₁₀₀ parent. Our experiments show that the acquisition of the MDR phenotype resulting from overexpression of P-glycoprotein in the plasma membrane does not effect the tumorigenicity of human CEM cells.

¹ Supported by the Leukemia Society of America (A. B. H., Special Fellow; J. M. T., Scholar); Public Health Service Grant CA-41183 and a grant from the Del Webb Foundation (J. M. T., A. B. H); Public Health Service Grant CA-40570 and American Lebanese Syrian Associated Charities (W. T. B).

² To whom repreint requests should be addressed.

Received 6/ 8/87. Revised 10/15/87. Accepted 10/23/87.