Studies of retinoids in the prevention and treatment of cancer.

Investigation of retinoids for anticancer activity in humans, either in the chemopreventive or treatment mode, has been little studied. We summarize here our ongoing investigations in four different areas: (1) secondary prevention of cervical dysplasia with topical application of all-trans-retinoic acid; (2) adjuvant treatment of resected high-risk stage I and II malignant melanoma with bacille Calmette Guérin (BCG) plus or minus oral vitamin A; (3) topical vitamin A acid therapy for cutaneous metastatic melanoma; an (4) oral isotretinoin as an anticancer agent

Concentration and synthesis of phosphoribosylpyrophosphate in erythrocytes from normal, hyperuricemic, and gouty subjects.

Phosphoribosylpyrophosphate (PRPP) synthetase activity and the intracellular concentration of PRPP were assayed in erythrocytes from patients with primary hyperuricemia and primary metabolic gout. Sensitivity of the enzyme to feed-back inhibition by adenosine diphosphate (ADP), guanosine diphosphate (GDP), and 2,3-diphosphoglycerate (2,3-DPG) was determined. All patients with gout and four of ten patients with hyperuricemia were taking allopurinol during the study. Mean PRPP synthetase activity in erythrocytes from hyperuricemic and gouty patients was similar to that in normal subjects, and feedback inhibition by ADP, GDP, and 2,3-DPG was intact. The concentration of PRPP in erythrocytes was higher in normal females than in normal males, higher in normal subjects than in gouty patients, and lower in hyperuricemic patients taking allopurinol than in those hyperuricemic patients not taking this drug. The difference in intracellular levels of PRPP in erythrocytes in gout versus hyperuricemic patients was not significant. The significance of these findings is discussed in relation to the regulation of PRPP synthetase and in the important regulatory role of PRPP in purine metabolism. © 1971

Role of topical tretinoin in melanoma and dysplastic nevi.

The retinoids have been investigated extensively as chemopreventive and therapeutic agents in a variety of neoplasms. They have been shown to inhibit the proliferation of transformed cell lines in vitro and transplanted tumors in vivo. In cultured murine melanoma cells, retinoids inhibit proliferation and induce differentiation. Human melanoma cell lines have shown a mixed response. The clinical experience with retinoids in melanoma has been limited. Previously we investigated the activity of topical B-all-trans-retinoic acid (Retin-A, vitamin A acid, retinoic acid, and tretinoin) against intracutaneous metastases from malignant melanoma. We saw complete remission of multiple lesions in one individual and regression of several lesions in a second patient. This experience led us to conduct the present pilot trial of topical tretinoin in dysplastic nevus syndrome. The latter is a precursor of malignant melanoma. We saw regression of some of the treated lesions to benign nevi showing minimal or no dysplasia. Thus topical tretinoin appears to possess some activity against melanoma and at least one of its precursor conditions. In view of these preliminary results, more extensive trials are warranted to better define the role of tretinoin in the chemoprevention of malignant melanoma in high-risk lesions

Effect of tumor colony definition on ionizing radiation survival curves of melanoma-colony forming cells.

Definition of survival and measurement of colony size in soft agar assays is important in establishing in vitro radiation survival curves. Conventionally, survival is assessed according to colony-forming ability. The distinction between small colonies that are abortive and those that are viable often involves a difficult and arbitrary choice for the investigator. We have examined the effect of different minimum colony sizes (greater than or equal to 25, greater than or equal to 50, greater than or equal to 75, and greater than or equal to 100 cells) on ionizing radiation survival curves for cells from established murine (CCL 53.1) and human (M1RW5) melanoma cell lines as well as from short-term human melanoma cell strains (C8146A, C8146C, C8161, C83-2C, C82-7A1, and C8442) and patient biopsy (83-4). Single cell suspensions were plated in the upper layer of the agar bilayer and cells were irradiated by single dose X rays. Giant cells did not form in colonies containing 50 or more cells. D0 values were highest (D0 values, from 390 to 100 cGy) for cells forming smaller colonies (greater than or equal to 25 cells, greater than or equal to 4-5 doublings) and lowest (D0 values, from 190 to 50 cGy) for cells forming larger colonies (greater than or equal to 100 cells, greater than or equal to 6-7 doublings). Therefore, apparent radiosensitivity was dependent on colony size selected for analysis. Precise measurement of colony size was important in establishing radiation survival curves because errors in determining the colony size will alter apparent radiosensitivity of cells. These results should help define the biological meaning of tumor colony growth in semisolid medium, and alter the interpretation of survival curves which measure sensitivity to agents using this assay

Vitamin A: evidence for its preventive role in human cancer.

Both the provitamin beta-carotene and natural vitamin A and its derivatives (the retinoids) are being proposed as potential chemopreventive agents. The biochemistry and pharmacology of vitamin A suggest a number of mechanisms whereby carcinogenesis can be affected. Epidemiologic studies have consistently demonstrated an increased relative risk of cancer for people with low vitamin A intake or low-to-normal serum retinol values. Chemoprevention trials in humans are only now beginning. In the interim, daily consumption of vitamin-A-containing foods may be a "prescription" worth following