Tumor induction in rats by feeding aminopyrine or oxytetracycline with nitrite

Abstract

Sprague-Dawley rats were given combinations of aminopyrine or oxytetracycline and sodium nitrite in drinking water. Of 30 animals receiving 0.1% (1,000 ppm) of aminopyrine and sodium nitrite for 30 weeks, 29 died with hemangioendothelial sarcomas of the liver. The same tumor caused death in 26 of 30 animals that received 0.025% (250 ppm) of both aminopyrine and sodium nitrite for 50 weeks. No animals in a control group of the same size that received 0.1% aminopyrine for 30 weeks developed this tumor, although one-half of them were still alive 2 years after the experiment was begun. After feeding a comparable dose (0.1%) of oxytetracycline and sodium nitrite for 60 weeks, liver tumors were present in 4 of 30 rats (3 hepatocellular tumors and 1 cholangioma). Since aminopyrine has been widely used for medicinal purposes in the human population, it is possible that many people have been exposed to a potent carcinogen (dimethylnitrosamine) by its formation in vivo. It is not certain whether the result of feeding oxytetracycline and sodium nitrite indicates significant carcinogenicity of this combination.

Recent advances in diverse nanosystems for nitric oxide delivery in cancer therapy

“…Understanding the antitumor properties of NO is of great significance for exploiting its role in tumor biology. This review comprehensively explains the antitumor mechanisms of NO from the following aspects ( Table 1 ) 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 .…”

“… Role of NO Mechanism of NO activity Ref. Causes genotoxicity Depolarization through mitochondria, caspase-3 activation and DNA fragmentation 55 , 56 , 57 , 58 , 59 , 60 Suppression of cellular respiration and shifts in iron metabolism Generation of oxygen free radicals Inactivation certain key enzymes in cell metabolism Promotes cancer cell apoptosis Decrease in BCL-2 expression 61 , 62 , 63 , 64 , 65 Promotion of the production of ceramide Macrophage activation P53 accumulation Inhibits cancer cell metastasis Decrease in galectin-3 expression Inhibition of platelet aggregation and tumor metastasis 66 , 68 , 69 Improves the efficacy of other drugs Upregulation of MMP-2 and 9 to loose tumor tissue structure 67 , 72 Destruction of the cell membrane to inhibit multidrug resistance Inhibition of the ATPase activity of P-gp to inhibit multidrug resistance Normalization of blood vessels at tumor sites to increase the penetration of chemotherapy drugs Reverses MDR Decreased expression of P-gp and MRP 70 , 71 , 73 Depletion of GSH Regulation of NF- κ B and HIF GSH, glutathione; HIF, hypoxia-induced factors; MDR, multidrug resistance; MRP, multidrug resistance related protein; NO, nitric oxide; P-gp, P-glycoprotein. …”

“…One of the mechanisms by which NO kills tumor cells is to damage DNA. NO can mediate DNA damage through any of the following three possible mechanisms: (i) the involvement of NO in a series of reactions that damage DNA 56 , 57 , 58 . (ii) Modification of DNA strands directly 84 , 85 ; and (iii) nitrosation of NO directly inhibits specific DNA repair systems.…”

Synthesis, spectral, theoretical, and antimicrobial screening of some heterocyclic oximes

“…Electron withdrawing groups (-NO, -CHO, -COR, and -CONHPh) introduced at the nitrogen atom profoundly affect the conformations of the heterocyclic ring and orientation of the substituents in 2,6-dialkyl-and 2,6-diarylsubstituted piperidines Harris and Spragg, 1969;Krishnakumar and Krishnapillay, 1996). It is also interesting to note that certain nitrosoamines have been reported to possess anticancer activities (Magee et al, 1976) and blocking the positions a to the ring nitrogen atom by methyl groups in cyclic nitrosoamines reduces the carcinogenic activity (Taylor and Lijinsky, 1975).…”

Challenges of HPLC method development and validation for the assay of combined drug products

“…this reaction to take place [36][37][38]. On the other hand, rectal administration of AMFZ completely eliminates the possibility of dimethylnitrosamine formation as the pH of the mucous fluid in that region is around 7.9.…”