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Molecular Targets in Oncology: Implications of the Multidrug Resistance Gene
Author(s) -
Lum Bert L.,
Gosland Michael P.,
Kaubisch Sonja,
Sikic Branimir I.
Publication year - 1993
Publication title -
pharmacotherapy: the journal of human pharmacology and drug therapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.227
H-Index - 109
eISSN - 1875-9114
pISSN - 0277-0008
DOI - 10.1002/j.1875-9114.1993.tb02695.x
Subject(s) - multiple drug resistance , vinca , vinblastine , etoposide , teniposide , vincristine , cancer research , pharmacology , doxorubicin , daunorubicin , cytotoxic t cell , drug resistance , p glycoprotein , biology , medicine , leukemia , chemotherapy , immunology , in vitro , cyclophosphamide , genetics
The curative potential of chemotherapy for a number of tumor types has been obscured by the fact that many patients initially have striking remissions but later relapse and die. At the time of relapse many patients manifest resistance to a wide array of structurally unrelated antineoplastic agents, hence the term multidrug resistance (MDR). Other tumor types, such as those arising in the colon, kidneys, liver, and lungs, tend to exhibit poor response to available cytotoxic drugs. The MDR phenomenon includes cross‐resistance among the anthracyclines (doxorubicin, daunorubicin), the epipodophyllotoxins (etoposide, teniposide), the vinca alkaloids (vinblastine, vincristine), taxol, and other compounds. In vitro studies in cell culture indicate that this form of resistance is associated with amplification or overexpression of the mdr l gene. The mdr l gene codes for the expression of a cell surface protein, P‐glycoprotein (P‐gp), which acts as an energy‐dependent efflux pump that transports drugs associated with MDR out of the cell before cytotoxic effects occur. The protein is expressed in normal human tissues such as the gastrointestinal tract, liver, and kidneys, where it is thought to serve as an excretory pathway for xenobiotic drugs and toxins. Preliminary studies demonstrated the presence of P‐gp in tumor samples from patients with acute leukemia, multiple myeloma, lymphomas, and a variety of solid tumors. A number of drugs are able to reverse MDR, including calcium‐channel blockers, phenothiazines, quinidine, antimalarial agents, antiestrogenic and other steroids, and cyclosporine. Limited results from clinical trials with small numbers of patients suggest that the addition of verapamil, diltiazem, quinine, trifluoperazine, or cyclosporine to chemotherapeutic regimens has the potential to reverse MDR; however, toxicities limit their clinical usefulness. A number of trials are under way to identify more active and less toxic modulators of MDR.