CisRetinoic Acid

In the mid-1980s the only retinoid available for clinical use was 13-cis-retinoic acid (13-cis-RA), which induced differentiation in promyelocytic leukemia, and produced objective clinical responses in promye-locytic leukemia, myelodysplastic syndrome, cutaneous T-cell lymphoma (mycosis fungoides), and advanced squamous carcinoma of the skin (Reynolds and Lemons 2001). Although 13-cis-RA has limited activity against established and progressing solid tumors, it was effective as a single agent in preventing second tumors in patients with head and neck carcinoma and preventing skin cancers in those with xeroderma pigmentosum.

Anecdotal trials of 13-cis-RA in NB showed responses of mass disease and marrow metastases, including a complete response with a 2-year remission in one patient (Reynolds et al. 1991). In a Children's Cancer Group (CCG) phase-II trial of single daily 100 mg/m2 day-1 of oral 13-cis-RA, 2 of 28 patients with refractory NB showed response (Finklestein et al. 1992). At this dose of 13-cis-RA, subsequent pharmacokinetic studies (Villablanca et al. 1995; Khan et al. 1996) demonstrated that drug levels obtained were below the 5- to 10-pM effective levels (Reynolds et al. 1994). The major toxicities of 13-cis-RA at the 100 mg/m2 day-1 dose were dryness of skin, dryness of mucous membranes, cheilitis, fissured lips, conjunctivitis, and hypertriglyceridemia.

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