Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:EXPT01586 (G418)
 2,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate whether marrow contributes to relapse after autologous bone marrow transplantation (AuBMT) for acute leukemia, transplanted marrow was marked with the G1N retroviral vector (Genetic Therapy Inc.) containing the neomycin phosphotransferase gene (neo). Between April 1992 and August 1993, 4 patients were transplanted for acute myeloid leukemia (AML) in second complete remission (CR) and 1 patient for acute lymphoid leukemia in first CR. An average of 12.4% (range 5-19%) of transplanted marrow mononuclear cells were exposed to G1N vector for 4 hr. In the vector-treated portion of the marrow, 4.9% of GM-CFU and 3.6% of erythroid burst-forming units (BFU-E) were resistant to G418 in vitro. In the 5 patients, the polymerase chain reaction (PCR) detected the neo sequence on only two occasions after AuBMT. Of 4 patients surviving 1 year after transplantation, only 1 had evidence of gene marked cells by PCR. Two AML patients have relapsed, one of whom had evidence of neo sequences in the bone marrow at day 100 but not at relapse 11 months after AuBMT. The second patient relapsed 18 months after AuBMT but never had PCR evidence of neo sequences before or after relapse. Our results indicate vector-transduced autologous bone marrow from heavily pretreated adults with acute leukemia mark with low efficiency, although vector sequences have been detected in bone marrow and peripheral blood up to 1 year after transplant. Of the 2 relapsed patients, no evidence of vector-marked leukemic blasts have been detected.
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PMID:Retroviral gene transfer in autologous bone marrow transplantation for adult acute leukemia. 881 19

In previous studies, we isolated a mutant DNA topoisomerase I cDNA from a camptothecin (CPT)-resistant human T-lymphoblastic leukemia cell line, CPT-K5, and demonstrated that an amino acid change from Asp to Gly at residue 533 is responsible for the CPT resistance of the enzyme. In the present study, we have constructed a bicistronic retroviral vector, Ha-TM1-IRES-neo, that carries the mutant (Gly-533) TOP1 cDNA (TM1) and a neomycin-resistance gene to examine the effect of mutant DNA topoisomerase I (topo I) expression on CPT resistance of cells. HeLa S3 cells were transduced with Ha-TM1-IRES-neo, and the transduced cells were selected with G418. Two independently isolated populations of the G418-resistant cells and 2 clones showed 1.7- to 1.8-fold higher resistance to CPT than the control cells. Integration and expression of the exogenous TOP1 were confirmed by genomic and RT-PCR analyses. The topo I enzyme (mixture of mutant and wild-type) expressed in the transduced cells showed 3-fold resistance to CPT in cleavable-complex-formation assay and DNA-relaxation assay. Mutant topo I activity in the transduced cells was as much as 10% that of the endogenous enzyme. Our results clearly show that expression of Gly-533 topo I confers a dominant form of CPT resistance in cells expressing wild-type topo I. The mutant TOP1 could be used for the protection of normal bone marrow cells of cancer patients from the severe hematotoxicity of CPT-derivative anti-tumor agents.
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PMID:Retroviral expression of a mutant (Gly-533) human DNA topoisomerase I cDNA confers a dominant form of camptothecin resistance. 1007 64