Pgp in cancer

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Drug resistance, either intrinsic or acquired, is a frequently encountered problem in the failure of antineoplastic agents. Pgp, an efflux pump that extrudes hydrophobic cytotoxic drugs from cancer cells, plays a key role in multidrug resistance (MDR) and may contribute to clinical drug resistance. Pgp is a 170 kDa cell-surface glycoprotein, encoded for by the MDR1 gene (Riordan & Ling 1985). The presence of MDR has been correlated with poor outcome in acute myeloid leukaemia, non-Hodgkin's lymphoma, acute lymphoblastic leukaemia and multiple myeloma (Arceci 1993, Fojo et al 1987, Goldstein et al

1989, Ro et al 1990, Pastan & Gottesman 1987, Epstein et al 1989, Herweijer et al

1990, Campos et al 1992). Many chemotherapeutic agents were also confirmed to be excellent substrates for the Pgp pump (Pastan & Gottesman 1987, Dorr et al 1987, Ford & Hait 1990, Epstein et al 1989, Herweijer et al 1990, Campos et al 1992). Many studies analysed the expression of Pgp in normal and malignant tissues and found that several tumours that showed high levels of expression of Pgp also seemed to show considerable clinical resistance to Pgp substrates — for example, colon cancer has very high levels of Pgp and is very resistant to doxorubicin, a Pgp substrate. It is also important to note that epithelial surfaces such as the biliary tract and gall bladder show high levels of Pgp and show chemoresistance to most drugs. Intrinsically resistant malignancies that are associated with high levels of Pgp are colon cancer, renal cell cancer, non-small-cell lung cancer, gliomas, meningiomas and primitive neuroectodermal tumours.

Many different resistance modulators have been identified to date, illustrated in Fig. 1. It is also now apparent that the mechanisms of resistance also differ with the different chemotherapeutic agents, and there may be several different mechanisms that are active simultaneously. Examples of the different resistance mechanisms which are in part responsible for clinical drug resistance are provided in Table 1. In addition to multiple mechanisms of drug resistance, it is also apparent that treatment will also induce resistance. Several studies have compared the level of

Subcellular redistribution

(altered drug binding, LRP)

Detoxification

(glutathione and associated enzymes)

Apoplosis

Subcellular redistribution

(altered drug binding, LRP)

Apoplosis

Cancer Multidrug Resistance

Tub u fin mutations

4 Drug uptake

(changes in lipid membrane composition)

Efflux pumps

T DNA repair

(CHS-methyi guanine methyl transferase)

FIG. 1. Potential mechanisms of drug resistance. Modified from Dalton et al (1993).

Efflux pumps

Altered drug target

(lopoi some rase

T DNA repair

(CHS-methyi guanine methyl transferase)

Tub u fin mutations

4 Drug uptake

(changes in lipid membrane composition)

FIG. 1. Potential mechanisms of drug resistance. Modified from Dalton et al (1993).

TABLE 1 Mechanisms of resistance to düerent chemotheraputic drugs

Drug

Mechanism of resistance

Doxorubicin, Daunorubicin, Idarubicin

Mitoxantrone

Vincristine

Melphalan

Etoposide

Paclitaxel

Pgp, MRP, LRP, topoisomerase II

Pgp, topoisomerase II

Pgp, tubulins

GSH/GST, LRP

Pgp, MRP, topoisomerase II

Pgp, tubulin mutations

Pgp expression at diagnosis and at relapse, with a fairly consistent trend showing increase in amount of Pgp with recurrence (Table 2).

Evidence to support the hypothesis that clinical resistance is dependent on Pgp expression in some malignancies was provided by the demonstration that Pgp expression could inversely correlate with response to therapy. This was elegantly demonstrated by Willman (1997), who evaluated 211 elderly patients with acute myeloid leukaemia and assessed both overall Pgp expression and functional

TABLE 2 Acquired drug resistance

TABLE 2 Acquired drug resistance

Disease

At diagnosis

A t relapse

AML

23

42

ALL

33

48

Myeloma

42

69

Lymphomas

14

52

Ovarian cancer

15

47

Breast cancer

0-50

30-85

Retinoblastoma

20

100

AML, acute myeloid leukaemia; ALL, acute lymphoblastic leukeamia.

AML, acute myeloid leukaemia; ALL, acute lymphoblastic leukeamia.

assessment of Pgp using rhodamine efflux (Table 3). The study shows that increased Pgp expression correlates with increased dye/drug efflux from leukaemia cells and both of these inversely correlate with likelihood of inducing remission. Del Poeta et al (1996) looked at survival in patients with acute myeloid leukaemia and found that patients had inferior survival if their disease was positive for Pgp. This applied equally in younger and elderly patients (Table 4).

The initial studies therefore pointed to a potentially major role for Pgp in causing clinical resistance and raised the intriguing possibility that overcoming or modulating Pgp would improve effectiveness of anticancer therapy. However, unless Pgp expression is modulated selectively in malignant tissues only, it is likely that normal tissue Pgp function will also be significantly affected and this could potentially increase treatment related toxicity.

TABLE 3 Correlation between Pgp expression, efflux and rate of CR

Pgp expression

CR rate (%)

Dyejdrugefflux

CR rate (%)

Negative

71

Negative

62

Low

54

Low

59

Intermediate

36

Intermediate

43

High

31

High

33

CR, complete remission.

CR, complete remission.

TABLE 4 Potential mechanisms of drug resistance in malignant cells

Mechanism

Effect

Drugs

Drug efflux pumps

Pgp, MRP — remove drug

Anthracyclines, vinca alkaloids,

from within cell

etoposide, taxanes

Decreased drug uptake

Changes in lipid membrane

Methotrexate, nitrogen

composition

mustard, melphalan,

cisplatin

Tubulin mutations

Alter sensitivity to taxanes/

Taxanes

chemotherapy

Altered drug target

Changes in levels of target

Methotrexate, anti-metabolites,

enzymes or alteration in

topoisomerase inhibitors

target

Subcellular redistribution

Altered drug binding

Apoptosis

Decreased ability to undergo

Alkylating agents, cisplatin,

apoptosis: Bcl2, p53, Fas

etoposide

antigen

Detoxification

Glutathione and associated

Cisplatin, alkylating agents

enzymes bind to drug

DNA repair

Repair damage induced by

Anthracyclines, alkylating

chemotherapy

agents, cisplatin

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Responses

  • alberica
    What is Pgp, MRP, and GST,LRP and efflux to rhodomine?
    8 years ago

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