Retinoids are a class of compounds structurally related to vitamin A. In preclinical studies, all-trans retinoic acid (tretinoin), 13-cis retinoic acid (isotretinoin) and the aromatic retinoids etretinate and acitretin have preventive and therapeutic effects on carcinogen-induced premalignant and malignant lesions. Clinically, chemoprevention with isotretinoin and etretinate has been tested with some degree of success in such indications as basal cell carcinomas, squamous cell carcinomas, superficial bladder tumors and second primary tumors in patients with squamous cell carcinoma of the head and neck. Limited therapeutic success has also been achieved with retinoid treatment of precancerous and cancerous conditions of the skin, oral cavity, larynx, lung, bladder and vulva. Dramatic therapeutic effects have been observed in the treatment of acute promyelocytic leukemia with tretinoin, which leads to very high rate of complete remission. Excellent results were recently reported in the treatment of squamous cell carcinomas of the skin and cervix with a combination of isotretinoin and recombinant interferon alfa-2a (rIFN alfa-2a, Roferon-A). The mechanism of action of retinoids is through modulation of cell proliferation and differentiation. Retinoids vary in their capacity to induce differentiation and to inhibit proliferation in a series of human transformed hematopoietic and epithelial cell lines. Some cytokines potentiate the retinoid-induced cell differentiation and act synergistically with retinoids to inhibit cell proliferation. The pattern of synergism is dependent upon the combination and tumor cell line tested. The discovery of nuclear retinoid receptors has contributed substantially to the understanding of the mechanism of action of retinoids at the molecular level. Further understanding of the molecular biology of retinoids is expected to contribute to a rational design of new retinoids in the future, which in turn may result in improvements in the prevention and therapy of cancer.
This review analysis consists of the antitumor activity and toxic deaths reported in single agent Phase I clinical trials using cytotoxic compounds published from 1972 to 1987. A total of 6639 patients with a variety of solid tumors and hematological malignancies were accrued in 211 trials studying 87 compounds. The median number of patients per trial was 28 (range: 7-111) and the median of the median ages reported in the individual trial was 56 (range of individual age: 2 to 93 years). Ten percent of the trials enrolled pediatric patients (less than 18 years), but the exact numbers of children were not always given or separated from the adult patients. Nine percent of the patients had received no prior treatment, 75% were pretreated either with chemotherapy alone (50%) or radio- plus chemotherapy (25%). Radiotherapy alone was administered to 11% of the patients and the remaining 5% of the patients received prior treatments which was not specified. The most frequent tumor types were those of the gastrointestinal tract (22%) and the respiratory tract (19%). The frequency of the remaining malignancies was less than 10% of all patients. There were 23 (0.3%) complete responders and 279 (4.2%) partial responders for an overall response rate of 4.5% among all entries. Toxic deaths were rare and reported in only 31 patients (0.5% of the entire population). Responses were usually observed in chemosensitive tumor types. Despite a low response rate reported during the first phase of cytotoxic drug development, the present analysis shows that some therapeutic benefit can be achieved.
A total of 178 patients with metastatic renal cell cancer were randomized to receive interferon alfa-2a (rIFN alfa-2a) or interferon alfa-2a+vinblastine (VLB). IFN alfa-2a was injected intramuscularly at a dose of 18 MIU 3 times a week and VLB was given intravenously at a dose of 0.1 mg/kg once every 3 weeks. The response rate was 11% for patients on monotherapy and 24% for those on combination treatment. The 5-year survival for 145 eligible patients was 9%, independently from the treatment arm. The performance status was significantly related to long-term prognosis, and 13% of the patients with performance status 0 were alive at 5 years, as compared to 6% and 0% for patients with a WHO grade of 1 and 2, respectively. The most frequent adverse events in both treatment arms were flu-like symptoms (95%), fatigue (70%) and gastrointestinal disturbances (68%). Leukopenia was observed more frequently with combination treatment (53%) than with IFN alfa-2a alone (30%). In conclusion, rIFN alfa-2a monotherapy at this dose and schedule has modest antitumor activity in metastatic renal cell cancer. The combination of rIFN alfa-2a+VLB results in a doubling of the response rate, but this does not translate into prolonged survival. Toxicity (except leukopenia) and tolerance were similar in both treatment arms.
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