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Biomedical subjects

W Bollag

Publications and source records attributed to W Bollag.

At least 55 records · Page 3Linked to original sources
PubMed1988

Therapeutic effect of the arotinoid Ro 15-0778 on chemically induced rat mammary carcinoma.

The arotinoid Ro 15-0778 (temarotene) is a third generation retinoid without a polar end-group. Established, palpable and measurable rat mammary tumours, chemically induced by oral administration of 12 mg/animal 7,12-dimethylbenz[a]anthracene, were treated with Ro 15-0778 as a feed-admix in daily doses of 100 mg/kg for 6 weeks and 200 and 400 mg/kg for 9 weeks. For comparison, tamoxifen (anti-oestrogen) was administered as a feed-admix in doses of 10 and 30 mg/kg/day for 9 weeks. Treatment with Ro 15-0778 resulted in a marked retardation of tumour growth in the groups treated with 100 and 200 mg/kg/day and in partial or even complete tumour regression in the group receiving 400 mg/kg/day. Tamoxifen treatment caused a transient tumour growth inhibition during weeks 1-5 with subsequent re-growth of mammary tumours. Both compounds were generally well tolerated. No signs or symptoms of hypervitaminosis A were noted with Ro 15-0778. One single convulsive attack occurred with 200 mg/kg/day of Ro 15-0778 and 400 mg/kg/day caused occasional convulsions in five out of 11 rats. The present investigation underlines the fact that the arotinoid Ro 15-0778 is not only a chemopreventive agent but also exerts a chemotherapeutic effect on established, chemically induced, mammary carcinomas of the rat.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Inhibition of rat mammary carcinogenesis by an arotinoid without a polar end group (Ro 15-0778).

The influence of an arotinoid without a polar end group (Ro 15-0778) on rat mammary carcinogenesis was investigated. Mammary tumors were induced by oral administration of 15 mg, 7,12-dimethylbenz-(a) anthracene (DMBA) to 50-day-old female Sprague-Dawley rats. Ro 15-0778 inhibited the development of mammary adenocarcinomas. The percentage of tumor-bearing rats, the mean number of tumors per rat as well as the mean total volume of tumors per rat were dose-dependently reduced by Ro 15-0778. The results are of particular interest, since this compound--probably because of the lack of a polar end group--does not induce the signs and symptoms of hypervitaminosis A. The inhibition of mammary cancer development by Ro 15-0778 compares favorably with that of N-(4-hydroxyphenyl) retinamide the hitherto most effective retinoid for prevention of chemically-induced mammary cancers in rats.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1987

Prevention and reversal by a non-polar arotinoid (Ro 15-0778) of 3,4-benzpyrene- and cigarette smoke condensate-induced hyperplasia and metaplasia of rodent respiratory epithelia grown in vitro.

A non-polar arotinoid, Ro 15-0778, has been investigated for its effect on carcinogen-induced changes in rodent respiratory epithelia in organ culture. In neonatal rat tracheas and fetal mouse lungs grown in vitro, 3,4-benzpyrene and cigarette smoke condensate induce an increased proliferation of epithelial cells associated with a loss of secretory activity and of ciliary function. These changes persist in the absence of carcinogens in explants transferred to control medium. Ro 15-0778 alone has no influence on the normal epithelial growth rate or normal differentiation. However, if combined with either benzpyrene or smoke condensate, the arotinoid antagonizes the carcinogen-induced hyperplasia and metaplasia. During simultaneous treatment, it prevents the increase in mitosis and the loss of secretory activity or ciliary function. In explants pretreated with benzpyrene or cigarette smoke condensate, Ro 15-0778 reverses the high proliferation rate and restores secretory differentiation and ciliary function. The compound is of experimental and clinical interest, since--in contrast to most retinoids--it lacks the signs and symptoms of the classical hypervitaminosis A syndrome. It may be justified to consider it for the treatment of early precancerous changes of the bronchial tree.

Animals↗
PubMed1986

Modulation of the effects of fluoropyrimidines on toxicity and tumor inhibition in rodents by uridine and thymidine.

Uridine and/or thymidine were administered concomitantly with 5-fluorouracil (5-FU) and 5'-deoxy-5-fluorouridine (5'-dFUR) to mice and rats in order to establish whether the physiological nucleosides acting in vitro as antagonists can diminish fluoropyrimidine toxicity in vivo. In addition, the influence of orally co-administered uridine on antitumor activity of 5-FU and 5'-dFUR in mice has been studied. All co-administrations aggravated the general toxicity of both fluoropyrimidines. Tumor inhibition was enhanced by uridine, but the therapeutic ratio was not improved compared to monotherapy with either 5-FU or 5'-dFUR.

Animals↗
PubMed1985

The effects of arotinoids on rat mammary carcinogenesis.

The influence of two retinoids, Ro 13-6298, an arotinoid ethyl ester, and Ro 15-1570, an arotinoid ethyl sulfone, on rat mammary carcinogenesis was investigated. Mammary carcinomas were induced by oral administration of 15 mg dimethylbenz(a)anthracene (DMBA) to 50-day-old female Sprague-Dawley rats. Oral administration of the two retinoids significantly inhibited the development of tumors. The number and volume of mammary neoplasms were influenced in a dose-dependent manner.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1984

Tumor specific conversion of a pyrimidine antimetabolite.

In order to explain the high differences of activity of 5'-dFUR and FUdR in the 4 tumor lines the conversion rate of the 2 nucleosides to the cytotoxic metabolite 5-FU was measured and compared with the conversion rate of uridine to uracil in tumor and liver homogenates. High activity of pyrimidine nucleoside phosphorylase was found in 5'-dFUR-sensitive tumor tissues. Conversion rates of uridine and 5'-dFUR were much lower in 5'-dFUR-insensitive tumors and in normal liver. This might at least partially explain the different responses to 5'-dFUR in vivo and in vitro.

Animals↗
PubMed1983

The development of retinoids in experimental and clinical oncology and dermatology.

The retinoids are a class of compounds consisting of vitamin A and its natural and synthetic analogues. Vitamin A has a marked influence on the differentiation of epithelial tissues, such as skin and mucous membranes. Vitamin A deficiency leads to hyperkeratosis of the skin and squamous metaplasia of mucous membranes, histologic features common to various dermatologic and precancerous diseases. The beneficial effect of vitamin A in these diseases was, however, unsatisfactory. Therefore, a retinoid program was set up in order to find new synthetic retinoids with the highest possible therapeutic activity and the least possible side effects. It was discovered that the chemically induced skin papilloma of the mouse responded to retinoids with a marked regression. This therapeutic activity in combination with the determination of a therapeutic index (relation between therapeutic action and hypervitaminosis A syndrome) served as criteria in choosing retinoids for clinical trials in dermatologic and oncologic diseases. Until now three particular compounds have achieved remarkable usefulness in dermatology: 13-cis-retinoic acid (isotretinoin; Accutane) in the treatment of cystic acne, the aromatic retinoid etretinate in the therapy of severe forms of psoriasis, and an arotinoid. Much less spectacular success has been achieved with these compounds in the prevention and therapy of premalignant and malignant diseases. It is hoped that newer retinoids with a still better therapeutic index or a more selective therapeutic activity will further enrich our therapeutic armamentarium in the fields of dermatology, oncology, and other disciplines of medicine.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1982

Phase I clinical study with 5'-deoxy-5-fluorouridine, a new fluoropyrimidine derivative.

5'-Deoxy-5-fluorouridine (DFUR) is a new fluoropyrimidine derivative with significant antineoplastic activity in animal systems. Compared to 5-FU or other fluoropyrimidines, DFUR has a more favorable therapeutic ratio in Sarcoma 180-bearing mice. DFUR was studied in this phase I trial with a daily x 5 bolus iv injection. A second course was given greater than or equal to 3 weeks after the first day of treatment. Doses were escalated from 300 to 5000 mg/m2/day in 30 patients. Dose-limiting factors were myelosuppression and stomatitis. Hematologic toxic effects were particularly marked on granulocytes. Thrombocytopenia was less frequently encountered. Stomatitis was severe at high doses of DFUR. Eleven patients had nausea or moderate vomiting. Drug-induced myocardial injury may exist, since electrocardiogram changes were recorded in two patients. After rapid iv injection, four patients felt hot in the face and pelvis. Other side effects were minimal. With this daily x 5 schedule of administration, the maximum tolerated dose of DFUR appeared to be 5000 mg/m2/day. The dose recommended for further clinical use is 4000 mg/m2/day x 5 for patients previously untreated with chemotherapy.

Adult↗
PubMed1982

Prevention and reversal by a retinoid of 3,4-benzpyrene- and cigarette smoke condensate-induced hyperplasia and metaplasia of rodent respiratory epithelia in organ culture.

The influence of an aromatic analog of vitamin A, etretinate, on the effects of 3,4-benzpyrene and cigarette smoke condensate has been investigated in fetal mouse lung and neonatal rat tracheas grown in organ culture. In both tissues, 3,4-benzpyrene as well as cigarette smoke condensate induces a striking increase of epithelial mitosis within 12--14 days of treatment. The increase is associated with a loss of secretory activity and of ciliary function. These changes persist in the absence of benzpyrene or smoke condensate in explants transferred to control medium. Treatment with etretinate alone does not affect the normal epithelial growth rate or normal differentiation. If combined with either benzpyrene or smoke condensate, the aromatic compound inhibits the increase in cell division and prevents the loss of secretory activity or ciliary function. In explants pretreated with 3,4-benzpyrene or cigarette smoke condensate, etretinate reduces the carcinogen- or smoke condensate-induced increase in mitotic activity to normal levels and restores secretory differentiation and ciliary function. The mechanism of action involved in the anticarcinogenic activity of the retinoid is discussed.

Animals↗
PubMed1981

Arotinoids. A new class of retinoids with activities in oncology and dermatology.

Arotinoids are a new class of retinoids with particular biological properties. Arotinoid Ro 13-6298 in minute quantities leads to regression of chemically induced papillomas of the skin of mice. The ratio between the antipapilloma effect and the toxic syndrome of hypervitaminosis A is very favorable. Ro 13-6298 also has a therapeutic influence on chemically induced skin carcinomas in mice. As the papilloma model has proved to be suitable for screening for antipsoriatic and antikeratinizing properties as well as for antineoplastic screening, arotinoids might be useful in human clinical dermatology and oncology.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1980

[5'-deoxy-5-fluoruridine, a new antineoplastic pyrimidine antimetabolite].

5'-deoxy-5-fluorouridine (5-DFUR) exerts a marked cytostatic activity, both intraperitoneally and orally, against experimental tumors. It has a strong antitumor effect on the Crocker sarcoma S 180, the Lewis lung carcinoma and a chemically induced squamous cell carcinoma of the skin. Its ratio of antitumor activity toxicity is more favourable than that of 5-fluorouracil, 2'-deoxy-5-fluorouridine and 1-(2-tetra-hydrofuryl)-5-fluorouracil. Mode of action and reasons for the favourable therapeutic ratio are discussed.

Animals↗
PubMed1980

Ultrastructural analysis of the retinoid-induced reversal of epithelial hyperplasia and metaplasia.

The 7, 12-dimethylbenzanthracene-induced skin papilloma of the mouse and the 3-methylcholanthrene-induced hyperplasia and metaplasia in prostate organ cultures were studied by electron microscopy. The two types of tissue both showed a reversal of hyperplasia and metaplasia when treated with retinoids (= vitamin A and analogs). This reversal was reached by means that are quite characteristic for a given type of tissue. In the skin, DNA-synthetic activity was not influenced by retinoid treatment. There was however, considerable necrosis and an impressive mucous metaplasia. The latter might be at least partly responsible for the cell loss, probably through a loss of anchorage in the prickle-cell layer. In the prostate, no mucous metaplasia was observed, but there was an important depression of DNA-synthetic activity. The secretory apparatus reappeared together with the microvilli, possibly induced by the slowing down of cell division.

Animals↗
PubMed1979

Retinoids and cancer.

The 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.

Animals↗
PubMed1978

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.

Animals↗