Retinoid-resistance

Mutants of the wild type S91-C2 melanoma cells have been isolated that are resistant to the antiproliferative action of retinoic acid (Lotan et al., 1983b). The mutant cells were also resistant to growth inhibition by retinol and a retinoidal benzoic acid derivative, suggesting a single growth-inhibitory mechanism common to all of these retinoids. Uptake of the retinoids was unimpaired in the mutant cells, and the cells had normal levels of CRABP. These results contrast with those of the retinoid-resistant embryonal carcinoma cell line mutants that were deficient in CRABP (Schindler et al., 1981). Eventually a mechanism of action of the retinoids will have to be described that can explain these diverse results, and mutants such as these should prove invaluable to such studies. 

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. 

Yen WC, Corpuz MR, Prudente RY, Cooke TA, Bissonnette RP, Negro-Vilar A, Lamph WW (2004) A selective retinoid X receptor agonist bexarotene (Targretin) prevents and overcomes acquired paclitaxel (Taxol) resistance in human non-small cell lung cancer. Clin Cancer Res 10(24) 8656-8664. 

Gorodeski GI, Eckert RL, Pal D, Utian WH, and Rorke EA [1997] Retinoids regulate tight junctional resistance of cultured human cervical cells. Am J Physiol 273 C1707-C1713... 

Benzofurotriazoles 353 were prepared and their activity in the inhibition of CYP26A1 evaluated in a MCF-7 cell assay. These compounds are analogues of the advanced pharmaceutical candidate liarozole, 354 <2006MIP308-86>. CYP26A1 catalyzes the metabolism of all-/ra j retenoic acid (ATRA) and is believed to be principally responsible for controlling the levels of this retenoid. Elevated levels of ATRA are used to treat hormone refractory prostate cancer and psoriasis. It is hoped that inhibition of CYP26A1 will limit the development of resistance to these retinoid treatments. 

Retinoids induce neoangiogenesis, whereas AHAs act on the dermis without necessarily going through a phase of inflammatory reaction. We can therefore assume that their combined effects can produce better results at the same time as reducing the incidence of side-effects thanks to the use of lower doses of each of these two potential irritants. For example, if there is resistance to (daily or twice daily) monotherapy with tretinoiff at 0.1%, applying an 8-10% glycolic acid gel beforehand helps the retinoid to penetrate more efticiently. Tretinoin and AHAs can be applied separately, but they can also be mixed in the same gel. 

Adverse effects of tetracyclines include resistant bacteria, folliculitis, candidiasis, gastrointestinal upset, and phototoxic effects. Tetracyclines must not be combined with systemic retinoids because of the increased probability for development of intracranial hypertension. Tetracycline is used in the treatment of moderate to severe acne vulgaris. It is the least expensive of the tetracyclines and therefore often prescribed for initial therapy. A common initial approach includes tetracycline 1 g daily (500 mg twice daily), 1 hour before meals after 1 or 2 months, when marked improvement of inflammatory lesions is observed, the dose may be decreased to 500 mg every day, for another 1 or 2 months. Drawbacks to the use of tetracycline include also a drug-food interaction with dairy prodncts. 

Freemanfle, S.J., Spinella, M.J. and Dmitrovsky, E. (2003) Retinoids in cancer therapy and chemoprevention promise meets resistance. Oncogene, 22, 7305-7315. 

Resistant strains of P. acnes are emerging that may respond to jndicions nse of retinoids in combination with antibiotics. Commonly nsed topical antimicrobials in acne inclnde erythromycin, clindamycin (Cleocin-t), and benzoyl peroxide and antibiotic-benzoyl peroxide combinations (Benzamycin, Benzaclin, others). Other antimiaobials nsed in treating acne inclnde sulfacetamide (Klaron), sulfacetamide/sulfur combinations (Snlfacet-R), metronidawie (Metrocream, Metro-Gel, noritate), and azelaic acid (Azelex). Systemic therapy is prescribed for patients with more extensive disease and acne that is resistant to topical therapy. Effective agents inclnde tetracycline (snmycin, others), minocycline (MINO-CIN, others), erythromycin (ERYC, others), clindamycin (CLEOCIN), and trimethoprim-sulfamethoxazole (bactrim, others). Antibiotics nsnally are administered twice daily, and doses are tapered after control is achieved. 

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