ANNUAL REVIEWS Annu.
Rev. Med. 1991. 42:277--/l6
Further
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MULTIDRUG RESISTANCE!
Annu. Rev. Med. 1991.42:277-284. Downloaded from www.annualreviews.org by University of California - Santa Barbara on 07/23/13. For personal use only.
Ira Pastan, M.D., and Michael M. Gottesman, M.D. Laboratory of Molecular Biology and Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 KEY
WORDS:
P-glycoprotein, doxorubicin, vinblastine, cancer, gene therapy, verapamil
ABSTRACT
Laboratory investigations indicate that cancer cells can become simul taneously resistant to many different chemotherapeutic drugs that are natural products via the expression of an energy-dependent drug efflux pump. This multidrug transporter is a plasma membrane glycoprotein encoded in the human by the MDRI gene. Recent clinical studies indicate that expression of the multidrug transporter plays a major role in the intrinsic and acquired resistance to chemotherapy of many human cancers. Strategies aimed at inactivating this drug efflux pump may have significant impact on the treatment of human cancer. Oncologists agree that one of the important unsolved problems in cancer treatment is drug resistance. This includes both intrinsic resistance at the time of initial chemotherapy and acquired drug resistance. In.a clinical setting, cytotoxic drugs are now given in various combinations and sched ules, both to try to avoid the emergence of resistant cells and to kill preexisting cells that already are drug resistant. To investigate the basis of drug resistance in the laboratory, drug-resistant cell lines have been iso lated by exposing various cancer cell lines to increasing amounts of chemo therapeutic agents. When the selecting drug is one of a group of the naturally occurring antibiotics shown in Table 1, for example adriamycin, I
The US Government has the right to retain a nonexclusive, royalty-free license in and to
any copyright covering this paper.
277
Annu. Rev. Med. 1991.42:277-284. Downloaded from www.annualreviews.org by University of California - Santa Barbara on 07/23/13. For personal use only.
278
PASTAN & GOTTESMAN
the resistant cells that are isolated are frequently not only resistant to adriamycin but may be cross-resistant to all members of that group. This simultaneous resistance to many different structurally unrelated drugs is called multidrug resistance (MDR). In its best-characterized form, MDR includes resistance to many natural products isolated from plants and microorganisms, but not resistance to agents synthesized in the laboratory such as cis-platin, cytosine arabinoside, cyclophosphamide, and metho trexate (1). The structures of several commonly used drugs belonging to the MDR family are shown in Figure I. Their lack of structural similarity is obvious. One common feature is that the drugs are moderately soluble in both water and lipid (amphipathic). Also, the drugs in the MDR group do not share a common mechanism of action; some affect microtubules and some inhibit DNA, RNA, or protein synthesis. The first clue to the biochemical basis of this type of resistance came from studies of drug transport showing that MDR cells accumulated less drug (2, 3). Drug entry appeared to be normal, but the cells had acquired the capacity to pump out the drugs (4; see Figure 3). There was no good precedent for a single transport protein that could pump such structurally diverse drugs out of cells, and many hypotheses were advanced to explain this puzzling process. The solution came when the gene responsible for MDR was isolated from a very highly drug-resistant cell line derived from a cervical carci noma. The methods used to isolate the gene have been described in detail elsewhere and are outside the scope of this review (5-7). The sequence of the amino acids encoded by the MDRI gene indicated it to be a membrane protein (also known as P-glycoprotein) composed of 1280 amino acids; many of the hydrophobic amino acids were embedded in the cell membrane in the form of twelve transmembrane domains that could be subdivided into two regions of six transmembrane domains each (Figure 2). ComTable 1
Drugs in the multidrug resistance group
Anticancer drugs
Other drugs
Actinomycin D
Colchicine
Daunomycin
Emetine
Doxorubicin
Ethidium bromide
Etoposide (VP-16)
Gramicidin D
Mitoxantrone
Mithramycin
Taxol
Puromycin
Teniposide (VM-26)
Valinomycin
Vinblastine Vincristine
MULTIDRUG RESISTANCE o
279
o
OH
OHl..
R
DAUNOMYCIN
R-CH:!
AORIAMYCIN
R-CH;9i
VINBLASTINE R _ CH3
Annu. Rev. Med. 1991.42:277-284. Downloaded from www.annualreviews.org by University of California - Santa Barbara on 07/23/13. For personal use only.
VINCRISTINE R. CHO
H R"\-o �
Rev. Med. 1991. 42:277--/l6
Further
Quick links to online content
MULTIDRUG RESISTANCE!
Annu. Rev. Med. 1991.42:277-284. Downloaded from www.annualreviews.org by University of California - Santa Barbara on 07/23/13. For personal use only.
Ira Pastan, M.D., and Michael M. Gottesman, M.D. Laboratory of Molecular Biology and Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 KEY
WORDS:
P-glycoprotein, doxorubicin, vinblastine, cancer, gene therapy, verapamil
ABSTRACT
Laboratory investigations indicate that cancer cells can become simul taneously resistant to many different chemotherapeutic drugs that are natural products via the expression of an energy-dependent drug efflux pump. This multidrug transporter is a plasma membrane glycoprotein encoded in the human by the MDRI gene. Recent clinical studies indicate that expression of the multidrug transporter plays a major role in the intrinsic and acquired resistance to chemotherapy of many human cancers. Strategies aimed at inactivating this drug efflux pump may have significant impact on the treatment of human cancer. Oncologists agree that one of the important unsolved problems in cancer treatment is drug resistance. This includes both intrinsic resistance at the time of initial chemotherapy and acquired drug resistance. In.a clinical setting, cytotoxic drugs are now given in various combinations and sched ules, both to try to avoid the emergence of resistant cells and to kill preexisting cells that already are drug resistant. To investigate the basis of drug resistance in the laboratory, drug-resistant cell lines have been iso lated by exposing various cancer cell lines to increasing amounts of chemo therapeutic agents. When the selecting drug is one of a group of the naturally occurring antibiotics shown in Table 1, for example adriamycin, I
The US Government has the right to retain a nonexclusive, royalty-free license in and to
any copyright covering this paper.
277
Annu. Rev. Med. 1991.42:277-284. Downloaded from www.annualreviews.org by University of California - Santa Barbara on 07/23/13. For personal use only.
278
PASTAN & GOTTESMAN
the resistant cells that are isolated are frequently not only resistant to adriamycin but may be cross-resistant to all members of that group. This simultaneous resistance to many different structurally unrelated drugs is called multidrug resistance (MDR). In its best-characterized form, MDR includes resistance to many natural products isolated from plants and microorganisms, but not resistance to agents synthesized in the laboratory such as cis-platin, cytosine arabinoside, cyclophosphamide, and metho trexate (1). The structures of several commonly used drugs belonging to the MDR family are shown in Figure I. Their lack of structural similarity is obvious. One common feature is that the drugs are moderately soluble in both water and lipid (amphipathic). Also, the drugs in the MDR group do not share a common mechanism of action; some affect microtubules and some inhibit DNA, RNA, or protein synthesis. The first clue to the biochemical basis of this type of resistance came from studies of drug transport showing that MDR cells accumulated less drug (2, 3). Drug entry appeared to be normal, but the cells had acquired the capacity to pump out the drugs (4; see Figure 3). There was no good precedent for a single transport protein that could pump such structurally diverse drugs out of cells, and many hypotheses were advanced to explain this puzzling process. The solution came when the gene responsible for MDR was isolated from a very highly drug-resistant cell line derived from a cervical carci noma. The methods used to isolate the gene have been described in detail elsewhere and are outside the scope of this review (5-7). The sequence of the amino acids encoded by the MDRI gene indicated it to be a membrane protein (also known as P-glycoprotein) composed of 1280 amino acids; many of the hydrophobic amino acids were embedded in the cell membrane in the form of twelve transmembrane domains that could be subdivided into two regions of six transmembrane domains each (Figure 2). ComTable 1
Drugs in the multidrug resistance group
Anticancer drugs
Other drugs
Actinomycin D
Colchicine
Daunomycin
Emetine
Doxorubicin
Ethidium bromide
Etoposide (VP-16)
Gramicidin D
Mitoxantrone
Mithramycin
Taxol
Puromycin
Teniposide (VM-26)
Valinomycin
Vinblastine Vincristine
MULTIDRUG RESISTANCE o
279
o
OH
OHl..
R
DAUNOMYCIN
R-CH:!
AORIAMYCIN
R-CH;9i
VINBLASTINE R _ CH3
Annu. Rev. Med. 1991.42:277-284. Downloaded from www.annualreviews.org by University of California - Santa Barbara on 07/23/13. For personal use only.
VINCRISTINE R. CHO
H R"\-o �
