Possible role of acetaldehyde in ethanol-related rectal cocarcinogenesis in the rat.

Prospective epidemiologic studies have reported an increased risk of rectal cancer following chronic ethanol ingestion. The effect of ethanol on chemically induced colorectal carcinogenesis is controversial depending on the experimental conditions. In the present study the effect of chronic ethanol administration on acetoxymethylmethylnitrosamine-induced rectal cancer and the possible role of acetaldehyde in this process were investigated. Chronic ethanol administration resulted in an earlier occurrence of rectal tumors in this animal model. Because the concomitant administration of cyanamide, a potent acetaldehyde dehydrogenase inhibitor, showed a positive trend toward increased incidences of tumors, acetaldehyde could be involved in the ethanol-associated carcinogenesis. To measure colonic acetaldehyde, 12 chronically ethanol-fed and control rats received an acute dose of ethanol (2.5 g/kg body wt). The mucosal concentration of acetaldehyde was significantly higher in the rectum compared with the cecum (198 +/- 23 vs. 120 +/- 23 nmoles.g colon-1, p less than 0.05), but was not affected by chronic ethanol feeding. Furthermore, 6 germ-free rats had significantly lower acetaldehyde concentrations in the rectum (84 +/- 11 vs. 234 +/- 33 nmoles.g colon-1, p less than 0.01) and in the cecum (59 +/- 13 vs. 121 +/- 33 nmoles.g colon-1, p less than 0.05) compared with 6 conventional animals, and this was paralleled by the number of fecal bacteria in the 2 intestinal segments. In addition, to determine the effect of chronic ethanol feeding on colorectal cell turnover, 30 animals were pair-fed liquid diets. Using the metaphase-arrest technique, alcohol feeding induced rectal (19.1 +/- 2.0 vs. 9.1 +/- 1.8 cells.crypt-1.h-1, p less than 0.01), but not cecal (18.9 +/- 1.3 vs. 22.2 +/- 3.3 cells.crypt-1.h-1, p greater than 0.05) hyperregeneration. This was accompanied by an increase in the crypt proliferative compartment and increased mucosal ornithine decarboxylase activity (63 +/- 18 vs. 22 +/- 6 pmoles.hr-1.mg protein-1, p less than 0.05). The data show that chronic ethanol ingestion accelerates chemically induced rectal carcinogenesis and raise the possibility that acetaldehyde probably generated through bacterial ethanol oxidation may be involved in this process. The secondary hyperregeneration of the mucosa, observed after alcohol feeding, could by itself favour carcinogenesis.

Efficacy of new ruthenium complexes against chemically induced autochthonous colorectal carcinoma in rats.

SD rats bearing acetoxymethylmethylnitrosamine-induced colorectal carcinomas were treated by i.v. administration of trans-imidazolium-bisimidazoletetrachlororuthenate (III) ImH(RuIm2Cl4), bisbenzimidazolium-benzimidazolepentachlororuthenate (III) (BzImH)2(RuBzImCl5) and trans-indazolium-bisindazoletetrachlororuthenate (III) In-dH(ruInd2Cl4). The dose levels used were 0.022 mmol/kg body weight administered twice weekly over ten weeks for all compounds and, additionally, 0.015 mmol/kg for ImH(RuIm2Cl4). All compounds caused a tumor growth inhibition exceeding 90%; differences were found with regard to toxicity: ImH(RuIm2Cl4 and (BzImH)2(RuBzImCl5) caused dose-related decreases in body weight and increases in mortality as shown by 21% and 29% body weight loss compared to controls as well as 10% and 45% mortality for the two dosages of the first compound, and 9% body weight loss compared to controls as well as 7% mortality for the latter compound. In contrast, equimolar administration of IndH(RuInd2Cl4) was not related to any symptoms of toxicity as evidenced by 2% body weight gain compared to controls as well as 0% mortality. Since this latter drug obviously showed remarkable activity in a highly resistant type of tumor at negligible toxicity, it certainly deserves special attention.

Technique for long-term infusion into the inferior mesenteric artery of unrestrained rats.

A technique for long-term infusion into the inferior mesenteric artery was developed which allows simple and reliable regional infusion into the colorectal segment of unrestrained rats. The cannulation system consists of an injection port 'In Stoppers' as a flow swivel, connected to an injection needle, which is inserted into a polyethylene tube protected by a steel spiral. During infusion the animals are free to move in the cage with access to food and water ad libitum. The method is suitable for regional chemotherapy as well as for studies of colorectal tumours in rats. In this study 73% of the cannulae remained functional for continuous infusion over a 15 day period.

Alkyl phosphocholines: toxicity and anticancer properties.

The study reports on the investigation of acute and subacute toxicity and on antineoplastic activity of hexadecylphosphocholine (HPC), the first compound of a new class of antineoplastic chemotherapeutics. In rats, the LD50 of HPC was 606 mumol/kg; the maximum tolerable dose over four weeks was 39 mumol/kg. Symptoms of toxicity were enteritis, spider cell activation in the liver, hemosiderosis in the spleen and reversible transaminase increase. The best therapeutic effect was observed on methylnitrosourea (MNU)-induced mammary carcinoma in the rat. Two transplantable mammary carcinomas in the rat and autochthonous benzo(a)pyrene-induced sarcomas exhibited low-grade sensitivity to HPC. The MXT mammary carcinoma of the mouse, the Walker 256 carcinosarcoma of the rat, and autochthonous acetoxymethylmethylnitrosamine-induced colonic tumors of the rat were not chemosensitive to HPC.

Paradoxical effect of dichlorobis(1-phenylbutane-1,3-dionato)molybdenum (IV), (Mo(bzac)2Cl2 on the growth of autochthonous chemically induced colorectal tumors in SD rats.

The influence of dichlorobis(1-phenylbutane-1,3-dionato)molybdenum (IV), (Mo(bzac)2Cl2) in acetoxymethyl-methylnitrosamine (AMMN) induced colorectal cancer in SD rats was assessed. Treatment was given intravenously twice a week for 10 weeks immediately after the end of the induction period (G1 and G2) or following coloscopic diagnosis of the tumors (G4, G5 and G6). Paradoxical therapeutic effect of Mo(bzac)2Cl2 on the growth the AMMN induced colorectal cancer was observed.

Comparative antitumor activity of ruthenium derivatives with 5'-deoxy-5-fluorouridine in chemically induced colorectal tumors in SD rats.

The activity of the newly synthesized ruthenium derivative imidazolium-bis(imidazole)tetrachlororuthenate (III) [ImH(RuIm2Cl4)] was compared with that of 5'-deoxy-5-fluorouridine (5'dFUR) in autochthonous acetoxy-methyl-methylnitrosamine (AMMN)-induced colorectal cancer in SD rats. Following coloscopic diagnosis of colorectal tumors treatment was administered twice weekly for a 10-week period. ImH(RuIm2Cl4) exhibited considerable antitumoral efficacy compared with 5'dFUR (20 T/C % and 60 T/C %, respectively) against the growth of AMMN-induced colorectal adenocarcinoma in SD rats. The mortality rates with ImH(RuIm2Cl4) were dose-related, but its efficacy did not vary in all doses administered.

Acetoxymethyl-methylnitrosamine (AMMN) induced colorectal carcinogenesis is stimulated by chronic alcohol consumption.

Chronic ethanol feeding together with the direct acting carcinogen AMMN led to an earlier occurrence of colorectal tumors in SD rats.

Autochthonous, acetoxymethylmethylnitrosamine-induced colorectal cancer in rats: a useful tool in selecting new active antineoplastic compounds?

Acetoxymethylmethylnitrosamine (AMMN)-induced autochthonous colorectal rat adenocarcinomas are an interesting model for the secondary evaluation of new antineoplastic compounds aimed at predicting clinical activity. These orthotopic tumors mimic the human situation closer than conventionally used transplanted systems with respect to their relatively slow growth, their genuine histology, their original tumor-host interaction and their low chemosensitivity to clinically used drugs. 4-Amino-N-(2' aminophenyl) benzamide, 4-Oxo-2-phenyl-4H-1-benzopyran-8-acetic acid, dichloro-bis(1-phenyl-1,3-butanedionato)titanium(IV) and diethoxy-bis(1-phenyl-1,3-butanedionato)titanium(IV) are four new agents, which have shown promising anticancer activity in this model, but which failed to show high activity in fast-growing transplanted systems. Clinical studies on these agents are highly warranted. A comparison of predicted and actual clinical anticancer activity will finally point to the appropriate means of drug selection.

Effect of interleukin-2 on the manifestation and growth of acetoxymethyl-methylnitrosamine-induced colorectal rat adenocarcinoma.

The effect of highly purified human interleukin-2 (IL-2) was assessed on acetoxymethyl-methylnitrosamine(AMMN)-induced colorectal Sprague-Dawley rat adenocarcinoma. Treatment was given for 5 weeks and started 5 weeks after a period of 10 weeks intrarectal administration of 2 mg/kg of AMMN once a week. Animals which showed no evidence of tumors by endoscopical examination of the gut were given 10,000 units/kg of IL-2 s.c. into the dorsal region 5 days a week. Blood samples were analyzed from half of the animals before and 72 h after the end of the treatment. The median tumor volume and the median tumor number per rat were lower in the treated group than in the control. A significant decrease in response to two mitogens (PHA, Con-A) was seen in tumor-bearing rats concomitantly with the tumor growth. The immunological suppression was not restored by treatment with IL-2. No differences in natural killer activity or interferon levels were detected between the control and the treated group. These data indicate some antitumor effect of IL-2 given before the manifestation of tumors in AMMN-induced colorectal rat adenocarcinoma.