Tumor production inhibition

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

It is clear that the effects of induction or inhibition of the metabolism will be complex because of the large number of possible metabolic pathways through which benzofalpyrene may be metabolized. For instance, the microsomal enzyme inducer 5,6-benzoflavone inhibits the carcinogenicity of benzofalpyrene in mouse lung and skin, whereas inhibitors such as SKF 525A may increase the tumor production from certain polycyclic hydrocarbons. 

It is widely accepted that retinoids inhibit tumor growth and development, or the promotional phase of tumorigenesis (1J5) since it is well known that vitamin A plays a marked, as yet ill-defined, role in controlling the growth and differentiation of epidermis and epidermally-derived structures (16-18). Experimental evidence for this hypothesis rests primarily on the observation that conditions of hypervitaminosis A significantly inhibit tumor production even when initiated after application of the carcinogenic insult. Thus, 13-cis-retinoic acid inhibits the induction of transitional cell... 

It appears that adenylosuccinate synthetase is subject to feedback and product inhibition by AMP, adenylosuccinate, GDP, and GMP. The KiS reported for AMP range from 10 to 3000 fx.M for the enzyme from normal cells from various sources 34, 38, 45, 50). The for AMP for adenylosuccinate synthetase from Novikoflf ascites and Walker carcinoma 256 tumors is in the range of 150-190 fiM and are less sensitive to inhibition than the acidic isozyme from rat liver for which the/f i for AMP was 47 /xM 45). In some cases, nucleoside monophosphates such as AMP interact with both nucleotide sites, producing noncompetitive inhibition patterns 38, 45). 

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