Involvement of MDR1 P-glycoprotein in multifactorial resistance to methotrexate
Murray D. Norris
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorDavid De Graaf
Department of Genetics, University of Illinois at Chicago, Chicago, IL 60612-7309, USA
Search for more papers by this authorCorresponding Author
Michelle Haber
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Michelle Haber, Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, High St., Randwick, Sydney, NSW, Australia 2031. Fax: (61) 2-399-8697
Eugene B. Mechetner, Oncotech Inc., 1791 Kaiser Ave, Irvine. CA 92714, USA
Search for more papers by this authorMaria Kavallaris
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorJanice Madafiglio
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorJayne Gilbert
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorEdward Kwan
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorBernard W. Stewart
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Eugene B. Mechetner
Department of Genetics, University of Illinois at Chicago, Chicago, IL 60612-7309, USA
Michelle Haber, Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, High St., Randwick, Sydney, NSW, Australia 2031. Fax: (61) 2-399-8697
Eugene B. Mechetner, Oncotech Inc., 1791 Kaiser Ave, Irvine. CA 92714, USA
Search for more papers by this authorAndrei V. Gudkov
Department of Genetics, University of Illinois at Chicago, Chicago, IL 60612-7309, USA
Search for more papers by this authorIgor B. Roninson
Department of Genetics, University of Illinois at Chicago, Chicago, IL 60612-7309, USA
Search for more papers by this authorMurray D. Norris
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorDavid De Graaf
Department of Genetics, University of Illinois at Chicago, Chicago, IL 60612-7309, USA
Search for more papers by this authorCorresponding Author
Michelle Haber
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Michelle Haber, Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, High St., Randwick, Sydney, NSW, Australia 2031. Fax: (61) 2-399-8697
Eugene B. Mechetner, Oncotech Inc., 1791 Kaiser Ave, Irvine. CA 92714, USA
Search for more papers by this authorMaria Kavallaris
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorJanice Madafiglio
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorJayne Gilbert
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorEdward Kwan
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorBernard W. Stewart
Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, Sydney, New South Wales, Australia
Search for more papers by this authorCorresponding Author
Eugene B. Mechetner
Department of Genetics, University of Illinois at Chicago, Chicago, IL 60612-7309, USA
Michelle Haber, Children's Leukaemia and Cancer Research Centre, Prince of Wales Children's Hospital, High St., Randwick, Sydney, NSW, Australia 2031. Fax: (61) 2-399-8697
Eugene B. Mechetner, Oncotech Inc., 1791 Kaiser Ave, Irvine. CA 92714, USA
Search for more papers by this authorAndrei V. Gudkov
Department of Genetics, University of Illinois at Chicago, Chicago, IL 60612-7309, USA
Search for more papers by this authorIgor B. Roninson
Department of Genetics, University of Illinois at Chicago, Chicago, IL 60612-7309, USA
Search for more papers by this authorAbstract
Cellular resistance to methotrexate (MTX) is believed to be unaffected by expression of MDRI P-glycoprotein (Pgp), a pleiotropic efflux pump acting on different hydrophobic compounds that enter cells by passive diffusion. A series of human leukemic CCRF-CEM sublines, isolated by multi-step selection for very high resistance to MTX, exhibit multiple mechanisms of MTX resistance, including decreased carrier-mediated uptake of MTX and DHFR gene amplification. These sublines show cross-resistance to drugs of the multi-drug resistance (MDR) family, which is correlated with relative resistance to MTX. The MTX-selected sublines show increased expression and function of the MDRI gene, based on the measurement of MDRI mRNA, Pgp and rhodamine 123 accumulation. Sequence analysis of the MDRI cDNA from MTX-selected CCRF-CEM cells revealed no mutations in the protein coding region. MTX resistance in these cell lines is partially reversible by a Pgp-specific monoclonal antibody (MAb) UIC2 and a monovalent Fab fragment of UIC2. Our results indicate that Pgp can contribute to multifactorial resistance to MTX. © 1996 Wiley-Liss, Inc.
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