M. Habs

Influence of disulfiram on the organotropy of the carcinogenic effect of dimethylnitrosamine and diethylnitrosamine in rats

In former studies in rats and mice it was shown that the acute toxicity of dimethylnitrosamine (DMNA) and diethylnitrosamine (DENA) is reduced by additional treatment with tetraethylthiuramdisulfide [(Disulfiram, Antabus® (DSF)]. In long-term experiments in 40 rats given 500 mg/kg DSF/ week the substance did not show carcinogenic effects, however, influenced the action of the nitrosamines. DENA, which was administered to 38 rats in a dosage of 20 mg/kg/week, induced liver tumors in 90% of the animals; in 29% besides some precancerous stages predominantly malignant carcinomas of the oesophagus were seen. DMNA when given to 31 rats in a dosage of 4 mg/kg/ week induced liver tumors in 55% of the animals. 26 rats were treated with a combination of 500 mg/kg DSF/week and 20 mg/kg DENA/week. In only 31% of the animals of this group liver tumors were found, however, 81% of them besides some precancerous stages showed predominantly carcinomas of the oesophagus. The combination of 500 mg/kg DSF/week and 4 mg/kg DMNA/week induced only 1 liver tumor (=3%) out of a group of 29 animals, whereas 59% of them showed squamous cell carcinomas of the paranasal sinus that were not seen when DMNA was given alone. Frühere Versuche an Ratten und Mäusen hatten gezeigt, daß die akute Toxicität von Dimethylnitrosamin (DMNA) und Diäthylnitrosamin (DÄNA) durch Behandlung der Tiere mit Tetraäthylthiuramdisulfid [Disulfiram, Antabus (DSF)] vermindert wird. Im chronischen Versuch an 40 Ratten wirkte DSF in einer Dosierung vom 500 mg/kg/Woche nicht carcinogen, seine Gabe beeinflußte aber die Wirkung der untersuchten Nitrosamine. DÄNA, an 38 Tieren in einer Dosierung von 20 mg/kg/Woche verabreicht, induzierte bei 90% der behandelten Ratten maligne Tumoren der Leber, in 29% wurden neben einigen prämalignen Formen überwiegend Carcinome des Oesophagus beobachtet. DMNA erhielten 31 Ratten in einer wöchentlichen Dosierung von 4 mg/kg/Woche. In dieser Gruppe zeigten sich bei 55% der Versuchstiere Tumoren in der Leber. 26 Ratten wurden mit einer Kombination von 500 mg/kg/Woche DSF und 20 mg/kg/Woche DÄNA behandelt. Nur bei 31% der Tiere dieser Gruppe ließen sich Tumoren im Bereich der Leber nachweisen, aber 81% von ihnen entwickelten neben einigen prämalignen Formen überwiegend Oesophaguscarcinome. Bei der kombinierten Applikation von 500 mg/kg DSF/Woche und 4 mg/kg DMNA/Woche fanden sich bei einer Tierzahl von 29 lediglich ein Tumor in der Leber (=3%), aber in 59% Plattenepithelcarcinome der Nasennebenhöhle; diese wurden bei alleiniger Gabe von DMNA nicht beobachtet.

Prevention of Urinary Bladder Tumors in Cyclophosphamide- Treated Rats by Additional Medication with the Uroprotectors Sodium 2-Mercaptoethane Sulfonate (Mesna) and Disodium 2,2'-Dithio-bis-ethane Sulfonate (Dimesna)

Cyclophosphamide (CP) was administered orally at a dose of 2.5 mg/kg body weight five times a week to 300 male Sprague‐Dawley rats in a carcinogenicity experiment. Four groups of 50 rats were treated with two different doses of sodium 2‐mercaptoethane sulfonate (mesna, Uromitexan) (single doses of 5 or 15 mg/kg body weight), or disodium 2,2′‐dithio‐bis‐ethane sulfonate (dimesna) (single doses of 12 or 35 mg/kg body weight), and the effect on carcinogenicity by cyclophosphamide was investigated. Two groups received mesna or dimesna only, and one additional group of 100 rats served as an untreated control. Evaluation of the study after 20 months proved CP to be carcinogenic, the induced neoplasms being in a variety of organs including tumors of the urinary bladder in 30% of the rats. The additional administration of mesna and dimesna significantly reduced the bladder tumor risk, this reduction being dose‐related. In the 100 rats treated with mesna or dimesna only, no evidence of a carcinogenic response or signs of other toxic effects were observed.

Reduction of carcinogenicity of N-nitrosomethylurea by indomethacin and failure of resuming effect of prostaglandin E2 (PGE2) against indomethacin

SummaryNonsteroid antiinflammatory drugs such as indomethacin may play an important role in preventing the development of chemically induced experimental carcinomas of various organs including the large bowel in rats and mice. This effect might correlate with an inhibition of prostaglandin (PG) synthesis by these drugs. Sprague-Dawley rats were given three intrarectal doses of 4 mg N-nitrosomethyl-urea (MNU) within week 1 to induce large-bowel carcinomas. The experimental groups of rats received a 0.001% aqueous solution of indomethacin ad libitum as drinking water for days 1–8 and/or a subcutaneous injection of 500 μg/kg body weight of PGE2 immediately before and 2 h after each MNU dose. They were then maintained on basal diet and plain tap water without further treatment. At autopsy at week 31, the tumor incidence and the mean number of tumors per rat were 90% and 1.7 in untreated rats, 67% and 0.8 in indomethacin-treated rats, and 79% and 1.2 in indomethacin+PGE2-treated rats, respectively. The data indicate that indomethacin reduced the number of large-bowel tumors, while pharmacologic doses of PGE2 failed to reestablish the anticarcinogenic activity of indomethacin. It was concluded that a tolerable therapeutic dose of indomethacin can reduce the carcinogenic activity of MNU in the large bowel.

Investigation of the tumorigenic response to benzo(a)pyrene in aqueous caffeine solution applied orally to Sprague-Dawley rats

SummaryIn a lifetime experiment benzo(a)pyrene (B(a)P) was administered to Sprague-Dawley rats either as an admixture to the diet or by gavage in an aqueous 1.5% caffeine solution. Dissolved benzo(a)pyrene induced more tumors of the forestomach than undissolved benzo(a)pyrene. The 1.5% caffeine solution (annual dose 27 g/kg) did not exert any carcinogenic activity under the conditions of this bioassay.

Carcinogenicity of methapyrilene hydrochloride, mepyramine hydrochloride, thenyldiamine hydrochloride, and pyribenzamine hydrochloride in Sprague-Dawley rats.

SummaryFour histamine antagonists, methapyrilene, thenyldiamine, mepyramine and pyribenzamine were tested for carcinogenicity in rats by continuous application in drinking water. Only methapyrilene displayed significant carcinogenic effects, inducing liver tumors in a dose-related pattern. Analogues not containing a thiophene ring (mepyramine, pyribenzamine) did not exhibit neoplastic effects under the experimental conditions.

Chemotherapy studies in autochthonous rat tumors intestinal cancer

Intestinal tumors in rats were induced by three different chemical carcinogens. Only tumors induced by 1,2-dimethylhydrazine responded slightly to combination chemotherapy of Adriamycin, Methotrexate, 5-Fluorouracil, and Cyclophosphamide. The same therapy failed in tumors induced by N-methyl-N′-nitro-N-nitroso-guanidine or acetoxymethyl-methyl-nitrosamine. These results and the comparability of chemotherapy in autochthonous tumors to experimental and clinical observations are discussed. Durch drei chemische Carcinogene wurden Darmtumoren bei Ratten induziert. Nur bei durch 1,2-Dimethylhydrazin induzierten Tumoren konnte eine schwache Reaktion auf eine Kombinationschemotherapie mit Adriamycin, Methotrexat, 5-Fluorouracil und Cyclophosphamid beobachtet werden. Das gleiche Therapieschema versagte bei durch N-Methyl-N′-Nitro-N-Nitroso-Guanidin und durch Acetoxymethyl-Methyl-Nitrosamin induzierten Tumoren. Diese Ergebnisse und die Vergleichbarkeit der Chemotherapie autochthoner Tumoren mit experimentellen und klinischen Beobachtungen werden diskutiert.

Carcinogenicity of acetoxymethyl-methyl-nitrosamine after subcutaneous, intravenous and intrarectal applications in rats.

In comparison to the known carcinogenic properties of Acetoxymethyl-Methyl-Nitrosamine (AMMN) after oral or intraperitoneal application the dimethylnitrosamine derivative was tested by subcutaneous, intravenous and intrarectal route in male Sprague-Dawley or Wistar rats. AMMN proved to be primarily a locally acting carcinogen. However, a second mode of action is indicated by systemic carcinogenic properties found after i.v. and s.c. applications. The lung and heart, and to a less extent the kidney and earduct were found as target organs of distant carcinogenic response. Vergleichend zu den bekannten carcinogenen Eigenschaften von Acetoxymethyl-Methyl-Nitrosamin (AMMN) nach oraler oder intraperitonealer Gabe wurde das Dimethylnitrosaminderivat in subkutaner, intravenöser und intrarectaler Applikation an männlichen Sprague-Dawley oder Wistar-Ratten geprüft. AMMN erwies sich als ein überwiegend lokal wirkendes Carcinogen. Zusätzlich ist ein zweiter Wirkungsmechanismus anzunehmen, da nach i.v. und s.c. Zufuhr systemische und carcinogene Eigenschaften auftraten. Lunge und Herz und weniger ausgeprägt die Niere und der Gehörgang erweisen sich als Trefferorgane der carcinogenen Wirkung entfernt vom Applikationsort.

Negative dose-response study for carcinogenicity of orally administered rutin sulfate in Sprague-Dawley rats

Rutin is a ubiquitous naturally occurring flavonoid, which is used in a number of drugs. It was tested for carcinogenicity in Sprague--Dawley rats as a water-soluble mixture of sodium salts of sulfuric acid esters. Over 2 years, doses ranging from 10 to 500 mg/kg body wt of rutin sulfate (expanding factor 2.66) were administered by gavage 3 times a week to 4 groups of rats comprising 12 males and 12 females each. A control group was treated with tap water. Age-adjusted analysis of tumor rates did not provide any evidence for rutin sulfate to be carcinogenic under the conditions of this bioassay.

Chemotherapy studies in autochthonous rat tumors

Acetoxymethyl-methyl-nitrosamine (AMMN) induced only carcinomas of the forestomach in female Sprague-Dawley rats after an induction time of about 100 days when applied orally twice weekly in single doses (d) of 3.5 mg/kg body weight. Butyl-butanol-nitrosamine (BBN) selectively produced bladder tumors in female Sprague-Dawley rats after about 280 days when given in daily oral single doses (d) of 10 mg/kg body weight. The reactions of a total of 520 rats with chemically induced tumors were tested using 4-drug combination chemotherapy with different equitoxic doses of Adriamycin (Adm), Methotrexate (Mtx), 5-Fluorouracil (5-FU) and Bleomycin (Blm). The influences of combined therapy on mean survival time, tumor weight, histology of tumors, and adverse side effects of therapy are herein described. The results showed to be tumorspecific. In addition, the comparability of experimental chemotherapy in autochthonous rat tumors to clinical experience is discussed. Innerhalb von 100 Tagen wurden mit Acetoxymethyl-methyl-nitrosamin (AMMN) selektiv Karzinome des Vormagens bei weiblichen Sprague-Dawley-Ratten erzeugt. Hierzu wurde AMMN zweimal wöchentlich in Einzeldosen (d) von 3,5 mg/kg oral verabreicht. Butyl-butanol-nitrosamin (BBN) rief bei weiblichen Sprague-Dawley-Ratten ausschließlich Papillome und Karzinome der Harnblase hervor, wenn diese chronisch oral mit einer Tagesdosis (d) von 10 mg/kg behandelt wurden. Die Tumorinduktionszeit lag bei 280 Tagen. An insgesamt 520 Ratten wurden die Auswirkungen einer Kombinationstherapie mit unterschiedlichen äquitoxischen Dosierungen von Adriamycin (Adm), Methotrexat (Mtx), 5-Fluoro-uracil (5-FU) und Bleomycin (Blm) untersucht. Als Parameter dienten die mittleren Lebenserwartungen, die Tumorgewichte und die Tumorhistologie. Nebenwirkungen der Kombinationstherapie werden mitgeteilt. Es zeigte sich ein tumorspezifisches Ansprechen auf die Therapie. Die Übertragbarkeit experimenteller Ergebnisse, die an autochthonen Rattentumormodellen gewonnen wurden, für die Klinik wird diskutiert.

Influence of five different postnatal lifelong treatments on the transplacental carcinogenicity of ethylnitrosourea in sprague-dawley rats

Sprague-Dawley rats received in 10 mg/kg body weight (group I) or 30 mg/kg body weight (group II) ethylnitrosourea (ENU) orally on the 19th day of pregnancy. Their offspring were treated with Bacille Calmette-Guerin, human albumin, hydrocortisone, cyclophosphamide or nicotine starting on the 6th day of life. The ENU treatment significantly reduced the life expectancy of all offspring. Treatment of the offspring did not influence tumor frequency, induction time or localization of neurogenic malignant tumors. Cyclophosphamide treatment of group II offspring increased the number of females bearing mammary carcinomas.