High-dose tamoxifen as an enhancer of etoposide cytotoxicity. Clinical effects and in vitro assessment in p-glycoprotein expressing cell lines

Abstract

Summary Twenty-six patients with relapsed or drug-resistant cancer were treated with a combination of oral etoposide (300 mg day-' for 3 days) and high-dose oral tamoxifen as a potential modulator of drug resistance (480 or 720mgday-' for 6 days beginning 3 days before etoposide). One patient with relapsed high-grade lymphoma and one with adenocarcinoma of unknown primary site has a partial response. Toxicity consisting of nausea, vomiting and subjective dizziness, unsteadiness of gait and malaise occurred during tamoxifen treatment. Serum levels of tamoxifen averaged 3-3.5 gM on day 4 of all courses of treatment at both 480 and 720 mg day-'. N-desmethyltamoxifen levels were lower than tamoxifen during the first course (2 JM) but increased to equal tamoxifen levels during the second course. Didesmethyltamoxifen levels remained below 1 gM. In vitro, both tamoxifen and the standard modulator of multidrug resistance, verapamil, produced minor enhancement of etoposide cytotoxicity in the MCF-7 wt cell line but produced no enhancement with any other cell line. High, intermittent doses of tamoxifen can be given with acceptable toxicity and produce serum levels that have been shown to modulate drug resistance in vitro. In vitro, however, such levels have no significant effect on etoposide cytotoxicity towards a range of wild-type and MDR cell lines.

The Phagocytosis of Rod Outer Segments is Inhibited by Selected Drugs in Retinal Pigment Epithelial Cell Cultures

“…Therapeutic doses of tamoxifen and toremifene cause serum concentrations of 3.0-3.5 mM for tamoxifen (Stuart et al 1992) and 2 mM for toremifene (Anttila et al 1990). Since the tissue levels of tamoxifen can be 10-60 times higher than their serum levels (Lien et al 1991), the concentrations used in the present study are within a relevant range.…”

Tamoxifen decreases drug efflux from liposomes: Relevance to its ability to reverse multidrug resistance in cancer cells?

“…This study indicates that the ability of tamoxifen to decrease drug efflux from liposomes, probably as a result of decreased membrane fluidity, is likely to contribute to the ability of tamoxifen to reverse MDR in cancer cells [16][17][18][19][20][21]24,25] through a similar basal mechanism for the decreased removal of cytotoxic drugs from the cancer cell. This is in addition to the ability of tamoxifen to inactivate the P-170 glycoprotein efflux pump that has evolved in cancer cells as a particular cause of MDR.…”

“…adriamycin) out of the cell, thus preventing the accumulation of drugs to an effective cytotoxic concentration. Tamoxifen has been shown to reverse P-170 glycoprotein-induced MDR in human and murine leukaemic cells [16] and in P-170 glycoprotein-expressing cell lines [17], and also vinblastine resistance in multidrugresistant cell lines [18]. In addition, tamoxifen can increase the cytotoxic effects of adriamycin and vinblastine *Corresponding author.…”

Differential modulation of doxorubicin toxicity to multidrug and intrinsically drug resistant cell lines by anti-oestrogens and their major metabolites

“…Patients receiving 'high dose' tamoxifen therapy (480 mg/day, Stuart et al, 1992) achieved plasma tamoxifen levels of 3.5 JIM, while total levels of tamoxifen and metabolites were -7 tLM. Although anti-oestrogens have been demonstrated to be -99% bound to plasma proteins such as alpha, acid glycoprotein (Chatterjee & Harris, 1990), these compounds are lipophilic cations and it is therefore likely that they accumulate to higher concentrations within the cell.…”