Neoplastic transformation, suppression

Imidazole antimycotics, ketoconazole, clotrimazole, and miconazole are potent inhibitors of various cytochrome P450-isoenzymes that also affect the metabolism of retinoids. They were fust shown to inhibit the metabolism of RA in F9 embryonal carcinoma cells. When tested in vitm liarazole, a potent CYP-inhibitor, suppressed neoplastic transformation and upregulated gap junctional communication in murine and human fibroblasts, which appeared to be due to the presence of retinoids in the serum component of the cell culture medium. Furthermore, liarazole magnified the cancer chemopreventive activity of RA and (3-carotene in these experiments by inhibiting RA-catabolism as demonstrated by absence of a decrease in RA-levels in the culture medium in the presence of liarazole over 48 h, whereas without liarazole 99% of RA was catabolized. In vivo, treatment with liarazole and ketoconazole reduced the accelerated catabolism of retinoids and increased the mean plasma all-irans-RA-concentration in patients with acute promyelocytic leukemia and other cancels. 

Tauchi, H., and Sawada, S., 1993, Suppression of gamma- and neutron-induced neoplastic transformation by ascorbic acid in Balb/c 3T3 cells, Int. J. Radiat. Biol. 63 369-374. 

Proposed role of gap junctional communication in retinoid-induced suppression of proliferation and inhibition of neoplastic transformation... 

These studies have thus demonstrated that the actions of retinoids as inhibitors of neoplastic transformation are highly correlated with their abilities to increase connexin 43 expression, increase GJC, decrease saturation density and suppress proliferation in confluent cultures. However, it must be noted that these are only correlations and cannot prove a cause and effect relationship. More recent studies have utilized molecular methodology to over-express connexin 43 in a variety of cell types without the requirement for retinoid treatment. As will be discussed later in this chapter, these studies are also highly supportive of the role of junctional... 

The studies discussed above have demonstrated that the induction of connexin 43 by retinoids and the consequent increase in homologous GJC between normal lOTl/2 cells, strongly correlates with the ability of these retinoids to suppress neoplastic transformation and increase... 

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