Interest has been increasingly focused on all-trans-retinoic acid (tRA) and 13-cis-retinoic acid (13cRA) in cancer chemoprevention and treatment. We have examined the in vitro effects of these 2 retinoic acids (

The expression of CD38 by B cells chronic lymphocytic leukemia (B-CLL) was studied in 20 untreated patients. The cells expressed abundant CD38 (relative fluorescence intensity range, 6 to 15) in 6 cases (group I patients), whereas CD38 expression was low to absent (relative fluorescence intensity range, 0 to 3) in the remaining cases (group II patients). Exposure of the cells from group I patients to goat antihuman mu chain antibodies (Ga mu-ab) resulted in the elevation of intracellular free Ca2+ concentration([Ca2+]i) followed by apoptosis. In contrast, exposure of group II cells to Ga mu-ab was not followed by increased levels of [Ca2+]i, programmed cell death or cell proliferation. No differences in the expression of surface IgM were noted in the two groups of B-CLL cells. Normal peripheral blood B cells, which expressed low to absent CD38, were capable of mobilizing [Ca2+]i and of proliferating after exposure to Ga mu-ab. The collected data suggest that, although group I B-CLL cells were able to transduce the signals delivered by IgM crosslinking, this pathway was severely impaired in group II B-CLL cells. However, unlike that observed in normal circulating B cells, stimulation of group I cells with Ga mu-ab resulted in apoptosis rather than proliferation. CD38 did not appear to be directly involved in [Ca2+]i mobilization induced by Ga mu-ab in group I B-CLL cells because their exposure to anti-CD38 monoclonal antibodies failed to cause [Ca2+]i mobilization or to block the [Ca2+]i response induced by Ga mu-ab. These data indicate that CD38 expression identified a particular subset of B-CLL cells with defined functional properties, including the propensity to undergo apoptosis.

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In this review, we aim to synthesize the emerging picture of retinoids in lung cancer through a summary of ongoing investigations in biology, chemoprevention and therapy settings, in an attempt to clarify the possible role of these agents in such a disease. Early work in head and neck cancer has evidenced the capability of retinoids to interrupt field carcinogenesis by reversing premalignant lesions and decreasing the incidence of second primary tumors (SPTs). At this time, the completed randomized trials in lung cancer have failed to demonstrate an evident chemopreventive effect of the tested agents on different study end points, although both a marginally significant benefit of retinol palmitate in time-to-development rates for smoke-related SPTs and a potential preventive effect of retinol supplementation against mesothelioma in selected populations of asbestos-exposed workers have been recently reported. Concerning the role of retinoids in lung cancer treatment, a moderate activity of 13-cis-retinoic acid (13cRA) or all-transretinoic acid (ATRA) as single agents has been reported in small series of advanced, mostly pretreated lung cancer patients. More encouraging findings derive from combination studies, in which retinoids, especially ATRA, are added to either alpha-interferon or chemotherapy and radiotherapy. Major recent advances have been made towards the understanding of retinoids mechanisms of action; at this regard, the role of RAR-beta basal or treatment-induced levels seems to be of particular interest as intermediate end point and/or independent prognostic factor, besides their known importance in lung carcinogenesis. Future research for chemopreventive and therapeutic programs with retinoids in lung cancer should be focused on the investigation of new generation compounds with a specificity for individual retinoid nuclear receptors. Such selective molecules may have a greater activity against lung cancer, with a more favourable toxicity profile, as recently suggested by our preliminary data on Ro 41-5253.

A panel of retinoids with different retinoid receptor profiles were investigated for their influence on cell proliferation, cell differentiation, apoptosis and angiogenesis. The results were correlated with the pattern of retinoid receptor transactivation of the tested pan-agonists and selective agonists. The retinoic acid receptor RARa plays a major role in mediating the properties of retinoids, which might contribute to the anti-tumor effect.Retinoids have been proven to be active agents in prevention and therapy of certain pre-neoplastic and neoplastic lesions (Bollag, 1995). However, in the majority of oncological indications treatment with retinoids remains inferior to conventional treatment. The efficacy of the known retinoids is too low and is not sufficiently selective for each tumor indication. In addition, therapy with these retinoids is impaired by their toxicity. Our efforts, therefore, have been centered on 2 directions: firstly, to improve efficacy and, secondly, to reduce the various signs and symptoms of hypervitaminosis A syndrome. Before the discovery of nuclear retinoid receptors, a series of effective retinoids had been found. In fact, all retinoids clinically useful to date in dermatological and oncological disease, such as all-trans retinoic acid (all-trans RA, tretinoin), 13-cis retinoic acid (13-cis RA, isotretinoin), etretinate and acitretin, were discovered by chemical manipulation of the vitamin A molecule and by biological testing in suitable pharmacological model systems. We are now, fortunately, in a position to complement the empirical approach by a rational approach based on our present knowledge of the molecular biology of the nuclear retinoid receptors.The pleiotropic action of retinoids might be explained mechanistically by the actions of the 6 known retinoid receptors, RARa, b, g, RXRa, b, g and their isoforms. Each receptor might mediate a set of unique biological functions in certain cells or tissue types. Thus, a retinoid ligand which binds and activates selectively one receptor subtype may have the desired individual biological property. Furthermore, the fact that there is tissue-specific expression of the receptor subtypes may allow therapeutic specificity through the use of receptor-selective ligands. To identify receptorselective ligands, hundreds of retinoids have been investigated for their binding affinity to the various receptors and their activation of these receptors.Our investigations have been performed to elucidate which retinoid receptor or co-operation of receptors might be responsible for a certain biological or pharmacological function. Besides determining directly the receptor profile needed for mediating a certain biological function, a selective receptor antagonist which counteracts the biological effect of the corresponding agonist has been employed to confirm the receptor specificity.Retinoids with varying receptor profiles have been brought into relationship with the following biological properties, which may potentially contribute to the desired anti...