Retinoic acid showed a preventive effect on the de- velopment of chemically induced mouse skin tumors. Papillomas and carcinomas were induced by topical application of dimethylbenzanthracene and croton

Abstract

I became interested in the relationship between vitaminA and cancer after intenseliterature studies, prompted by an article by U. Saffiotti eta!, in 1967 on inhibition oftracheobronchial carcinogenesis by vitamin A. 1 In the laboratories of Hoffmann-La Roche I observed that vitamin A exerted not only preventive but also therapeutic effects on chemically induced skin tumors of mice. The limitation for clinical use of vitamin A rested with its toxic side effects, known as hypervitaminosisA. Therefore, my working hypothesis wasas follows: By chemical manipulation of the vitamin A molecule, derivatives might be found, still possessing the desired preventive or therapeutic effect, but inducing fewer side effects. The first compound tested was the synthesized alltrans retinoic acid. Although this analog showed a better therapeutic index, this was far from satisfactory. By performing a lare synthetic program, my goal was to find analogs with a much more favorable ratio between tumor effect and toxicity. The Roche chemists, experienced in vitamin A chemistry, were in favor of the project. However, the vitamin biologists argued: “During millionsof years of evolution, nature has developed thebest suhstance looking for a better one wouldbe hopeless.” In reply, I discussed with them the analogy tothe field of steroids,where synthetic compounds had been found that displayed more selective therapeutic activity than the parent physiological substance. Eventually, Hoffmann.La Roche’s management decided in favor of the retlnoid project. I believe that the reason my paper on vitamin A acid (1972) and subsequently thoseon cancer chemopreventionand therapy with an aromatic retinoic acid analog 2 . 3 have been cited so frequently was succinctly expressed in 1976 by M.B. Sporn eta!.: “The first successful efforts which have demonstrated that synthetic retinoids can be more potent and less toxic than natural retinoids for prevention of cancer have very recently been made by Bollag.” 4

Cite this paper

@inproceedings{Bollag2002RetinoicAS, title={Retinoic acid showed a preventive effect on the de- velopment of chemically induced mouse skin tumors. Papillomas and carcinomas were induced by topical application of dimethylbenzanthracene and croton}, author={Werner Bollag}, year={2002} }