No abstract

No abstract

Retinoids have shown promise as anti-cancer and cancer preventative agents. All-trans-N-(4-hydroxyphenyl)-retinamide (4HPR) belongs to a new group of retinoids that not only inhibit the proliferation of cancer cells but also can induce apoptosis in certain cancer cells. Because of its increased efficacy against cancer cells and its low toxicity it has been entered into a number of clinical trials. However, its mechanism of action is not known, and it had been assumed that it is not a true retinoid. Here we analyze its ability to function as an activator of nuclear retinoid receptors (RARs and RXRs). We observe that, in transactivation assays, 4HPR is a potent transactivator with RAR␥ and a moderate activator with RAR␤ but is not an activator with RAR␣ and RXR␣. Furthermore, RAR␥-selective transactivation by 4HPR is enhanced on some response elements and reduced on others when compared to natural retinoids. In contrast to transactivation, 4HPR in transrepression assays functions mostly with RAR␣, RAR␤, and RXR␣. Optimal receptor activation is seen at 4HPR concentrations at which it is a potent growth inhibitor and inducer of apoptosis. We conclude that 4HPR is a highly selective activator of retinoid receptors. We propose that this selective activation of the nuclear receptors is likely to be the basis for its specific biological activities and its favorable pharmaceutical properties.

Decanal and N-amino-N'-1-octylguanidine (AOG), combined at 28 microM each, mediated erythrocyte lysis within 80 minutes under physiological conditions. By contrast, no lysis was observed after 20 hours with either decanal (56 microM) or AOG (100 microM) alone. The pronounced synergism observed for these chemicals and similar reactive pairs of chemicals is due to the self-assembly of more cytotoxic hydrazones in situ. Decanal and AOG also exhibit synergistic activity against cultured human cells (HeLa) and bacteria (Escherichia coli J96). This synergism may be useful in the design of cytotoxins that would self-assemble selectively from nontoxic precursors within tumors, while sparing normal tissue.

Taxol is a product isolated from the Pacific yew tree (Taxus brevifolia) and is a potent microtubule-stabilizing agent which has recently been approved for treatment of otherwise intractable ovarian cancer. Despite taxol's therapeutic promise, its aqueous insolubility (< 0.004 mg ml-1) hampers its clinical application. Here we report the design, synthesis and biological activity of a series of taxol-releasing compounds (protaxols) with improved pharmacological properties. These prodrugs were designed to increase their aqueous solubility and allow for taxol release under basic or physiological conditions. We demonstrate the stability of these prodrugs at pH < or = 7 and their ability to release taxol in a basic medium. Taxol-like microtubule-stabilizing activity appears after the release of taxol. In vitro these prodrugs have cytotoxic properties against tumour cell lines comparable to those of taxol; moreover, human plasma catalyses the release of active taxol. These protaxols have greater potential as anticancer agents than the parent compounds taxol and taxotere (Fig. 1a).