Nattsumi's Epilepsy Diary

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

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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