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The mechanism of P-gp multidrug resistance (MDR) involving anthracyclines was investigated using three charged anthracyclines, Adriamycin ADR, AD288 and AD198 of increasing lipophilicity and their 3'-deaminated (uncharged) counterparts, WP159, WP546 and WP549, respectively. The results revealed that highly lipophilic anthracyclines can overcome high levels of ADR resistance that is largely due to P-gp-mediated MDR and that they are localized predominantly in the cytoplasm and mitochondria. This allows circumvention of resistance mechanisms other than those due to P-gp-MDR. It was also evident that overcoming P-gp-MDR may be achieved through self-modulation exhibited by the highly lipophilic anthracyclines.

Tapiero H, Ba GN, Couvreur P, Tew KD. Biomed Pharmacother 2002;56:215-222. Linoleic and alpha-linolenic acids, obtained from plant material in the diet are the precursors in tissues of two families [...]

The natural female sex hormone estrogens binds once inside the cell to a protein receptor to form a ‘ligand-hormone receptor complex’. The binding activates the hormone receptor, which triggers specific cellular processes. The activated hormone receptor then turns on specific genes, causing cellular changes that lead to responses typical of a ligand-hormone receptor complex. Estrogens (especially estradiol) bring out the feminine characteristics, control reproductive cycles and pregnancy, influence skin, bone, the cardiovascular system and immunity. Natural hormones are more potent than any of the known synthetic environmental estrogens (except drugs such as diethylstilbestrol ⟦DES〉). Estrogen production varies according to different factors (gender, age and reproductive cycles). Women produce more estrogen than men and the production is more abundant during fetal development than in the postmenopausal period. Most natural estrogens are short-lived, do not accumulate in tissue and are easily broken down in the liver. In contrast to natural estrogens, estrogenic drugs such as ethynylestradiol diethylstilbestrol (DES), synthetic environmental estrogens such as ß-hexachlorocyclohexane (ß-HCH), polychlorinated biphenyls (PCBs), o, p, p’DDT, 4-nonylphenol (NP) and phytoestrogens such as isoflavones or lignans, are more stable and remain in the body longer than natural estrogens. Because most of these compounds are lipophilic, they tend to accumulate within the fat and tissue of animals and humans. Thus, depending on the natural estrogen levels, environmental estrogens may have different influences (mimicking, blocking or cancelling out estrogen’s effects) on estrogen activities. [Copyright &y& Elsevier]

Perturbations of cell proliferation and death are considered as essential events in the process of carcinogenesis. Thus, two parameters, ornithine decarboxylase (ODC), an enzyme closely related to cell proliferation and transformation, and apoptotic phenomenon are profoundly modified. Using Syrian hamster embryo (SHE) cells, we have examined in the framework of two-stage carcinogenesis (initiation-promotion) the effects of a non-genotoxic [diethylhexylphthalate (DEHP)] or genotoxic [benzo[a]pyrene (BaP)] carcinogen or a non-carcinogenic compound [phthalic anhydride (AP)] on these parameters. Immunoreactive Bcl-2 and Bcl-xL proteins were also investigated following two-stage exposures. Whereas exposures to BaP, DEHP or AP alone did not provoke any modification of ODC activity, the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), strongly increased it. Using two-stage exposure protocol (xenobiotics first, then replacement by TPA-promoter), the ODC activity was higher than that obtained with TPA alone. This superinduction of ODC activity was observed only with the carcinogenic compounds DEHP and BaP. Following the same exposure protocol, spontaneous cellular apoptosis was decreased. Furthermore, Bcl-2 oncoprotein was also upregulated approximately 8- and 11-fold for BaP and DEHP respectively; meanwhile Bcl-xL protein rate did not change. The non-carcinogenic compound AP slightly inhibited spontaneous SHE cell death without ODC superinduction. Exogenous polyamines, putrescine, spermidine and spermine diluted in the medium did not inhibit spontaneous apoptosis. Although inhibition of apoptosis was not specific of carcinogenic compound, both superinduction of ODC activity and inhibition of apoptosis via Bcl-2 upregulation, may cooperate during early stages of the carcinogenic process. [ABSTRACT FROM PUBLISHER]

We investigated the effect of DNA-repair-enzyme inhibitors on L-phenylalanine mustard (L-PAM) and cis-diamminedichloroplatinum (II) (CDDP) cytotoxicity in rat mammary-carcinoma MatB cells sensitive (WT) and resistant (MLNr) to bifunctional alkylating drugs. Among the modulators tested, the combination of arabinofuranosylcytosine (Ara-C) and hydroxyurea (HU) significantly increased the sensitivity of the cells to CDDP and, to a lesser extent, L-PAM as compared with cells treated with drug alone. The modulation effect of HU+Ara-C on CDDP and L-PAM cytotoxicity was more effective when intracellular glutathione (GSH) was depleted by L-buthionine-(S,R)-sulfoximine (BSO). This was also associated with a significant increase in DNA-DNA interstrand cross-links. Caffeine also sensitized both WT and MLNr cells to the cytotoxic effect of L-PAM and CDDP, and this effect was potentiated in GSH-depleted cells. No significant effect was observed with other repair modulators such as aphidicolin, 3-aminobenzamide, novobiocin, or etoposide. These results show (a) that inhibition of DNA repair by HU+Ara-C or caffeine could be a target for modulation of bifunctional alkylating-drug resistance and (b) that GSH depletion renders resistant cells more susceptible to the repair-enzyme modulators, suggesting that intracellular GSH may be involved in the regulation of some of these enzymes. Our results also indicate that a combination of a number of modulators may offer an advantage over the use of a single modulator in tumor resistance that may be associated with multifactorial mechanisms. [ABSTRACT FROM AUTHOR]