Werner Bollag

Prophylaxis of chemically induced benign and malignant epithelial tumors by vitamin A acid (retinoic acid)

Abstract The prophylactic effect of retinoic acid on the development of chemically induced papillomas and carcinomas of the skin of mice was examined. The tumors were induced by local application of dimethylbenzanthracene and croton oil. Retinoic acid— 200 mg/kg every 14 days—was administered orally during the promotion phase of carcinogenesis. It delayed the appearance, retarded the growth and lead to regression of papillomas. The induction of carcinomas was also inhibited. By prophylactic administration of retinoic acid the appearance of carcinomas was delayed and their incidence reduced.

Retinoids, a new class of compounds with prophylactic and therapeutic activities in oncology and dermatology.

A review of recent investigations in the retinoid field is presented. Retinoic acid exerts a prophylactic and a therapeutic effect on chemically induced benign and malignant epithelial tumors in mice. In clinical studies positive therapeutic results have been obtained in patients with preneoplastic and neoplastic epithelial lesions. However, treatment with retinoic acid is limited by serious side effects (hypervitaminosis A syndrome). Therefore, the synthesis of analogs of retinoic acid (retinoids) possessing a more favorable therapeutic ratio has been initiated. Among a large series of synthesized compounds, certain aromatic analogs proved to have a particularly favorable therapeutic ratio. The structure-activity relationship of the most active retinoids is discussed including some biological data concerning prophylaxis and therapy of epithelial tumors. The total synthesis of retinoids according to various building schemes is discussed in detail. Methods for the synthesis of the cyclic end group, of the polyene chain component, and of the full retinoid skeleton are described. Metabolic studies of retinoic acid and of the most active retinoid, as well as the synthesis of some isolated metabolites are outlined. Suggestions concerning the mechanism of action of retinoids are made. Some clinical results on the treatment of acne, psoriasis and precancerous conditions are reported.

Therapeutic effects of an aromatic retinoic acid analog on chemically induced skin papillomas and carcinomas of mice

Abstract Retinoic acid has been shown to exert a prophylactic and a therapeutic effect on chemically induced premalignant and malignant epithelial lesions. The development of hypervitaminosis A is the dose limiting factor in its experimental and clinical use. The biological properties of the aromatic retinoic acid analog: ethyl all-trans- 9 -( 4 -methoxy- 2,3,6 -trimethylphenyl)- 3,7 -dimethyl- 2,4,6,8 -nonateraenoate(=I) were examined. The systemic administration of this compound leads to a marked regression of carcinogen iduced established skin papillomas and carcinomas of mice. A method is described for screening of the dissociation between papilloma regression and hypervitaminosis A production. I possesses a therapeutic ratio which is ten times more favorable than that of retinoic acid. The investigation has proven that the antipapilloma effect is not strictly linked with hypervitaminosis A. This raises hopes for finding compounds with an even better therapeutic ratio, useful in the experimental and clinical prophylaxis and therapy of premalignant and malignant epithelial lesions. The mechanism of action is discussed.

Retinoids and cancer.

SummaryThe early and recent investigations in the field of retinoids and cancer are reviewed. The retinoids, including natural vitamin A compounds and their synthetic analogs, present a new class of substances exerting a prophylactic and a therapeutic effect both in certain experimental tumor models and in certain clinical conditions of preneoplastic and neoplastic lesions. Because of a particular physiological mechanism of action, the retinoids offer a new approach to the cancer problem, which is different from those of surgery, X-ray therapy, conventional chemotherapy, and immunotherapy.

Effects of ALL-trans-retinoic acid and 13-cis-retinoic acid on breast-cancer cell lines: Growth inhibition and apoptosis induction

Interest has been increasingly focused on all‐trans‐retinoic acid (tRA) and 13‐cis‐retinoic acid (13cRA) in cancer chemoprevention and treatment. We have examined the in vitro effects of these 2 retinoic acids (RAs) on human breast‐cancer cell lines MCF‐7 and ZR‐75.1 (both estrogen‐receptor‐positive, ER+) and MDA‐MB‐231 (estrogen‐receptor‐negative, ER−), in terms of inhibition of proliferation and induction of apoptosis. Both retinoic acids exerted an evident dose‐dependent growth inhibition, although in the ER− cell line the anti‐proliferative effect was obtained only with the highest concentration used; the anti‐proliferative activity of tRA was more evident than 13cRA on all 3 tested cell lines. tRA and 13cRA induced apoptosis in MCF‐7 and MDA‐MB‐231 cell lines, but not in ZR‐75.1. The apoptotic phenomenon was clearly time‐dependent, and in our experience it was not related to the arrest in a specific phase of cell cycle. After treatment with RAs the levels of bcl‐2 were reduced in MCF‐7, while in ZR‐75.1 and in MDA‐MB‐231 no treatment‐related modifications were observed. An analysis of estrogen‐receptor status, used as a marker of differentiation, demonstrated that after treatment with RAs the levels of estrogen receptor (ER) decreased in ZR‐75.1 only. Our study indicates that the anti‐proliferative effects of RAs are sustained by induction of apoptosis in MCF‐7 and MDA‐MB‐231 cells, while in ZR‐75.1 cells an induction of differentiation without apoptosis was the prevalent mechanism of growth inhibition. Our results encourage further studies on in vivo effects of these retinoids in breast cancer.Int. J. Cancer 70:619–627.

Tumor inhibitory effects of a new fluorouracil derivative: 5′-deoxy-5-fluorouridine

Abstract 5 ′-Deoxy- 5 -fluorouridine ( 5 -DFUR) has a high cytostatic activity, both intraperitoneally and orally against experimental tumors. It has a particularly strong antitumor effect on the Crocker sarcoma S 180 , the Lewis lung carcinoma and a chemically induced squamous cell carcinoma of the skin. Its effect was less marked on the leukemia L 1210 and the B- 16 melanoma. The ratio between antitumor activity and toxicity is more favourable than that of 5 -fluorouracil, 2 ′-deoxy- 5 -fluorouridine and 1-(2 -tetrahydrofuryl)- 5 -fluorouracil.

Prophylaxis of chemically induced epithelial tumors with an aromatic retinoic acid analog (Ro 10-9359)

Abstract An aromatic analog of retinoic acid, ethyl all-trans- 9 -( 4 -methoxy- 2,3,6 -trimethylphenyl)- 3,7 -dimethyl- 2,4,6,8 -nonatetraenoate (= Ro 10-9359 ), has been found to possess a prophylactic effect on the development of skin papillomas and carcinomas of mice induced by 7,12 -dimethylbenzanthracene and croton oil. The daily oral application of 30 mg/kg Ro 10-9359 —given during the promotion phase of carcinogenesis-delayed the appearance and retarded the growth of papillomas and reduced the incidence of carcinomas. Considering the low toxicity of Ro 10-9359 , its preventive action on epithelial tumors is very remarkable.

The degradation of deoxyribonucleic acid by new tumour inhibiting compounds: The intermediate formation of hydrogen peroxide

Methylhydrazinderivate wie 1-Methyl-2-p-(isopropylcarbamoyl) benzyl-hydrazin-hydrochlorid und 1-Methyl-2-p-allophanoylbenzyl-hydrazin-hydrobromid bewirken unter aeroben Bedingungen einen Viskositätsabfall der wässerigen Lösungen von Desoxyribonucleinsäure. Es wird gezeigt, dass dieser Effekt auf die Bildung von Wasserstoffperoxyd bei der Autoxydation der Methylhydrazinverbindungen zurückzuführen ist. Auf die Analogie zum indirekten Effekt von Röntgenstrahlen wird hingewiesen.

Inhibition of tumor cell-induced angiogenesis by retinoids, 1,25-dihydroxyvitamin D3 and their combination

Tumor-induced angiogenesis (TIA), i.e., the ability of transformed cells to stimulate new blood vessel formation is an important factor contributing to tumor growth and invasiveness. The antiangiogenic effect of the retinoids, all-trans retinoic acid, 13-cis retinoic and 9-cis retinoic acid, of 1,25-dihydroxyvitamin D3, and of their combinations were studied using an experimental system in vivo. TIA was induced in immunosuppressed mice by intradermal injection of the two human transformed keratinocyte lines, Skv-e2, harboring DNA of human papillomavirus (HPV) type 16, and HeLa, harboring HPV18 DNA. The three retinoids and 1,25-dihydroxyvitamin D3, when administered systemically to mice, before the angiogenesis assay significantly decreased TIA. Their combination led to a synergistic inhibition of TIA. These results provide the basis for the use of combination of retinoids and 1,25-dihydroxyvitamin D3 in treatment of neoplastic diseases.

Tumour inhibitory effects of a new class of cytotoxic agents: Methylhydrazine derivatives

Die tumorhemmende Wirkung einer neuen Klasse von Cytostatica (Methylhydrazinderivate) wird beschrieben. Das Wachstum des Ehrlich-Carcinoms in solider und ascitischer Form, des Crocker Sarkoms S 180, des Walker-Carcinosarkoms 256 und des Uterus-Epithelioms T 8 wird deutlich gehemmt. 1-Methyl-2-p-(isopropylcarbamoyl)benzyl-hydrazin-hydrochlorid (I) und 1-Methyl-2-p-allophanoylbenzyl-hydrazin-hydrobromid (II) zeichnen sich durch besonders starke cytostatische Aktivität aus.