Mechanisms of drug resistance in chemotherapy for urogenital carcinoma

Seiji Naito, Akira Yokomizo, Hirofumi Koga

Research output: Contribution to journalReview article

50 Citations (Scopus)

Abstract

Cancer chemotherapy is the principal approach for urogenital cancers. However, the acquisition of resistance to anticancer agents is a critical factor that limits the successful treatment of malignancies. The multidrug resistant (MDR) phenotype has been widely recognized in cancer chemotherapy in urogenital tumors and the mechanisms underlying MDR have also been extensively studied. One of the principle mechanisms in MDR is caused by the overexpression of P-glycoprotein (P-gp), encoded by the multidrug resistance gene (MDR1). It functions as an ATP-dependent active efflux pump of chemotherapeutic agents in human cancer cells. Recently, other drug resistance proteins, including multidrug resistance-associated protein (MRP1) and cMOAT (or MRP2), were also identified from multidrug resistant cells. A functional analysis of MRP1 has shown that MRP1 may have the potential to act as a transporter of glutathione conjugates, which has been known as a central detoxification pathway in anticancer agents. Furthermore, several other resistance-related proteins (e.g. glutathione S-transferase, metallothionein, thioredoxin, topoisomerase I, II, O6-alkylguanine-DNA methyltransferase, etc.) have been found to be up- or down-regulated in resistant cells and these molecules are believed to contribute to the resistant phenotype as well. Based on the molecular characteristics identified in MDR, several experimental and clinical approaches have been studied to overcome MDR. One of these strategies is to reverse MDR by using such P-gp inhibitors as verapamil and cyclosporine A. In this review, we summarize the recent advances in MDR-related molecules and clinical trials to circumvent MDR in urogenital carcinomas.

Original languageEnglish
Pages (from-to)427-439
Number of pages13
JournalInternational Journal of Urology
Volume6
Issue number9
DOIs
Publication statusPublished - Sep 20 1999

Fingerprint

Drug Resistance
Carcinoma
Drug Therapy
P-Glycoprotein
Neoplasms
Antineoplastic Agents
Urogenital Neoplasms
MDR Genes
Multidrug Resistance-Associated Proteins
Phenotype
Type II DNA Topoisomerase
Type I DNA Topoisomerase
Thioredoxins
Metallothionein
Methyltransferases
Verapamil
Glutathione Transferase
Cyclosporine
Proteins
Adenosine Triphosphate

All Science Journal Classification (ASJC) codes

  • Urology

Cite this

Mechanisms of drug resistance in chemotherapy for urogenital carcinoma. / Naito, Seiji; Yokomizo, Akira; Koga, Hirofumi.

In: International Journal of Urology, Vol. 6, No. 9, 20.09.1999, p. 427-439.

Research output: Contribution to journalReview article

Naito, Seiji ; Yokomizo, Akira ; Koga, Hirofumi. / Mechanisms of drug resistance in chemotherapy for urogenital carcinoma. In: International Journal of Urology. 1999 ; Vol. 6, No. 9. pp. 427-439.
@article{714fd310e1c44164858498ff0b36d31f,
title = "Mechanisms of drug resistance in chemotherapy for urogenital carcinoma",
abstract = "Cancer chemotherapy is the principal approach for urogenital cancers. However, the acquisition of resistance to anticancer agents is a critical factor that limits the successful treatment of malignancies. The multidrug resistant (MDR) phenotype has been widely recognized in cancer chemotherapy in urogenital tumors and the mechanisms underlying MDR have also been extensively studied. One of the principle mechanisms in MDR is caused by the overexpression of P-glycoprotein (P-gp), encoded by the multidrug resistance gene (MDR1). It functions as an ATP-dependent active efflux pump of chemotherapeutic agents in human cancer cells. Recently, other drug resistance proteins, including multidrug resistance-associated protein (MRP1) and cMOAT (or MRP2), were also identified from multidrug resistant cells. A functional analysis of MRP1 has shown that MRP1 may have the potential to act as a transporter of glutathione conjugates, which has been known as a central detoxification pathway in anticancer agents. Furthermore, several other resistance-related proteins (e.g. glutathione S-transferase, metallothionein, thioredoxin, topoisomerase I, II, O6-alkylguanine-DNA methyltransferase, etc.) have been found to be up- or down-regulated in resistant cells and these molecules are believed to contribute to the resistant phenotype as well. Based on the molecular characteristics identified in MDR, several experimental and clinical approaches have been studied to overcome MDR. One of these strategies is to reverse MDR by using such P-gp inhibitors as verapamil and cyclosporine A. In this review, we summarize the recent advances in MDR-related molecules and clinical trials to circumvent MDR in urogenital carcinomas.",
author = "Seiji Naito and Akira Yokomizo and Hirofumi Koga",
year = "1999",
month = "9",
day = "20",
doi = "10.1046/j.1442-2042.1999.00088.x",
language = "English",
volume = "6",
pages = "427--439",
journal = "International Journal of Urology",
issn = "0919-8172",
publisher = "Wiley-Blackwell",
number = "9",

}

TY - JOUR

T1 - Mechanisms of drug resistance in chemotherapy for urogenital carcinoma

AU - Naito, Seiji

AU - Yokomizo, Akira

AU - Koga, Hirofumi

PY - 1999/9/20

Y1 - 1999/9/20

N2 - Cancer chemotherapy is the principal approach for urogenital cancers. However, the acquisition of resistance to anticancer agents is a critical factor that limits the successful treatment of malignancies. The multidrug resistant (MDR) phenotype has been widely recognized in cancer chemotherapy in urogenital tumors and the mechanisms underlying MDR have also been extensively studied. One of the principle mechanisms in MDR is caused by the overexpression of P-glycoprotein (P-gp), encoded by the multidrug resistance gene (MDR1). It functions as an ATP-dependent active efflux pump of chemotherapeutic agents in human cancer cells. Recently, other drug resistance proteins, including multidrug resistance-associated protein (MRP1) and cMOAT (or MRP2), were also identified from multidrug resistant cells. A functional analysis of MRP1 has shown that MRP1 may have the potential to act as a transporter of glutathione conjugates, which has been known as a central detoxification pathway in anticancer agents. Furthermore, several other resistance-related proteins (e.g. glutathione S-transferase, metallothionein, thioredoxin, topoisomerase I, II, O6-alkylguanine-DNA methyltransferase, etc.) have been found to be up- or down-regulated in resistant cells and these molecules are believed to contribute to the resistant phenotype as well. Based on the molecular characteristics identified in MDR, several experimental and clinical approaches have been studied to overcome MDR. One of these strategies is to reverse MDR by using such P-gp inhibitors as verapamil and cyclosporine A. In this review, we summarize the recent advances in MDR-related molecules and clinical trials to circumvent MDR in urogenital carcinomas.

AB - Cancer chemotherapy is the principal approach for urogenital cancers. However, the acquisition of resistance to anticancer agents is a critical factor that limits the successful treatment of malignancies. The multidrug resistant (MDR) phenotype has been widely recognized in cancer chemotherapy in urogenital tumors and the mechanisms underlying MDR have also been extensively studied. One of the principle mechanisms in MDR is caused by the overexpression of P-glycoprotein (P-gp), encoded by the multidrug resistance gene (MDR1). It functions as an ATP-dependent active efflux pump of chemotherapeutic agents in human cancer cells. Recently, other drug resistance proteins, including multidrug resistance-associated protein (MRP1) and cMOAT (or MRP2), were also identified from multidrug resistant cells. A functional analysis of MRP1 has shown that MRP1 may have the potential to act as a transporter of glutathione conjugates, which has been known as a central detoxification pathway in anticancer agents. Furthermore, several other resistance-related proteins (e.g. glutathione S-transferase, metallothionein, thioredoxin, topoisomerase I, II, O6-alkylguanine-DNA methyltransferase, etc.) have been found to be up- or down-regulated in resistant cells and these molecules are believed to contribute to the resistant phenotype as well. Based on the molecular characteristics identified in MDR, several experimental and clinical approaches have been studied to overcome MDR. One of these strategies is to reverse MDR by using such P-gp inhibitors as verapamil and cyclosporine A. In this review, we summarize the recent advances in MDR-related molecules and clinical trials to circumvent MDR in urogenital carcinomas.

UR - http://www.scopus.com/inward/record.url?scp=0032885328&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032885328&partnerID=8YFLogxK

U2 - 10.1046/j.1442-2042.1999.00088.x

DO - 10.1046/j.1442-2042.1999.00088.x

M3 - Review article

C2 - 10510888

AN - SCOPUS:0032885328

VL - 6

SP - 427

EP - 439

JO - International Journal of Urology

JF - International Journal of Urology

SN - 0919-8172

IS - 9

ER -