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Retinoids clinical studies

There is now compelling evidence from the number of retinoids in the clinic and in clinical studies (Table 12.1) that these molecules exhibit efficacy in human diseases. The use of ATRA for the treatment of acute promyelocytic leukemia is considered a successful therapy in our view. It is the hope that the application of retinoids, most probably more receptor specific retinoids/rexinoids, in combination with other chemotherapeutic agents, will lead to broad clinical utility in many diseases. We anticipate that the retinoid field will continue to expand as researchers gain more information about new levels of retinoid/rexinoid biology and their relevance to human diseases. [Pg.399]

Table 102.1 Summary of data from clinical studies investigating the effect of retinoids on radioiodine uptake... [Pg.995]

Clinical studies in the use of retinoic add for the treatment or chemoprevention of cancers are becoming more common. Of particular interest has been the use of natural retinoids for the treatment of APL [101,102,193,194,236-241], also called acute non-lymphocytic leukaemia type M3 (ANLL-M3) and French-American-British criteria for M3 leukaemia (FAB M3). The incidence of reports of attainment of complete remissions in patients treated with RA has dramatically increased over the past few years. The following paragraphs describe some of the results obtained to date. Lastly, a brief summary of other studies on the effect of RA in cancer prevention/treatment will be given. [Pg.43]

The normal levels of retinoic acid in human plasma have been determined to be approximately 10 M (De Ruyter et al., 1979 De Leenheer et al., 1982). However, clinical studies with 13-c/y-retinoic acid have demonstrated that plasma concentrations as high as 10 M are attainable in man following oral dosing with the retinoid (Frolik et al., 1978). Therefore it is reasonable to assume that 13-cw-retinoic acid may have useful applications in promoting erythropoiesis or granulopoiesis in clinical situations. [Pg.221]

From in vitro studies it has been shown that systemic retinoids may decrease endothelial proliferation [37]. Recently, the beneficial effect of systemic tretinoin in patients with HIV-related Kaposi s sarcoma was reported in first pilot clinical studies [6]. As shown in cutaneous T cell lymphomas, it seems that retinoids and interferons may act synergistically. The mechanisms underlying this synergistic effect were thought to be an induction of the expression of RARs and, vice versa, the expression of interferon-receptors by retinoids. Therefore, combination therapy of HIV-related Kaposi s sarcoma with interferon a and systemic tretinoin may be a promising concept. [Pg.256]

Most recently, a phase-I-study defined a dose of 13-ris-retinoic acid that was tolerable in patients after myeloablative therapy, and a phase-III-trial showed that postconsolidation therapy with 13-cis-retinoic acid improved EFS for patients with high-risk neuroblastoma [7]. Preclinical studies in neuroblastoma indicate that ATRA or 13-cw-RA can antagonize cytotoxic chemotherapy and radiation, such that use of 13-cis-RA in neuroblastoma is limited to maintenance after completion of cytotoxic chemotherapy and radiation. It is likely that recurrent disease seen during or after 13-cis-RA therapy in neuroblastoma is due to tumor cell resistance to retinoid-mediated differentiation induction. Studies in neuroblastoma cell lines resistant to 13-cw-RA and ATRA have shown that they can be sensitive, and in some cases collaterally hypersensitive, to the cytotoxic retinoid fenretinide. Here, fenretinide induces tumor cell cytotoxicity rather than differentiation, acts independently from RA receptors, and in initial phase-I-trials has been well tolerated. Clinical trials of fenretinide, alone and in combination with ceramide modulators, are in development. [Pg.1076]

Diugs with metabolic interactions that can enhance the half-life of active compounds. An example of this regimen is the interaction between azole- and vitamin D-deiivatives that inhibit the metabolism of retinoids in skin cells leading to increased intracellular amounts of active RA-isomers. Further study and the identification of novel interactions of this type ofdtug interaction is of great clinical interest since they may decrease the dose of retinoids required for efficacy thereby also reducing the risk of side effects of the retinoids. [Pg.1078]

All of these metabolites possess retinoid activity that is in some in vitro models more than that of the parent isotretinoin. However, the clinical significance of these models is unknown. After multiple oral dose administration of isotretinoin to adult cystic acne patients (18 years of age and older), the exposure of patients to 4-oxo-isotretinoin at steady state under fasted and fed conditions was approximately 3.4 times higher than that of isotretinoin. In vitro studies indicated that the primary P450 isoforms involved in isotretinoin metabolism are 2C8, 2C9, 3A4, and 2B6. Isotretinoin and its metabolites are further metabolized into conjugates, which are then excreted in urine and feces. [Pg.2034]

CRA has been detected in humans [34] and was the first RAR-RXR pan-agonist discovered [35-37] and may be classified as a retinoid/rexinoid. It is the only retinoic acid isomer not approved for the common dermatological diseases. However, it has recently been launched in the US as adjuvant topical treatment of AIDS-associated Kaposi s sarcoma [38-41]. This agent is the first RXR ligand to be approved for the treatment of a dermatological disease. In a randomized study with 268 AIDS-associated Kaposi s sarcoma patients, 35% treated with alitretinoin (0.1% gel) had a positive response, compared with 18% treated with vehicle gel irrespective of the number of concurrent antiretroviral therapies [41], 9-CRA is in clinical trials for the treatment of various cancers, including breast cancer [42], renal cell carcinoma [43,44] and squamous cell carcinoma [45—47]. [Pg.394]


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See also in sourсe #XX -- [ Pg.7 , Pg.994 ]

See also in sourсe #XX -- [ Pg.43 ]




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