Amethopterin toxicity

Table 4 Quantitative comparison of Amethopterin toxicity in mice, rats, hamsters, dogs.

Isted by adminisiiation of AT-methylformainide, carbon tetrachloride, or azaserine (S16). It is of interest that fasting to a d ree which brings about loss in body wei t equivalent to that brought about by amethopterin also stimulated the incorporation of formate-C into add-soluble adenine (SIS). The formate stimulation produced by the amethopterin and the other treatments may be a manifestation of hepato toxicity (Hid). Increased labeling, correlated with amethopterin toxicity, has been found to occur only with liver (1B16). Schrecker et al. 217) have compared the effects of amethopterin and its 3, 5 -dichloro derivative (DCM) on the incorporation of formate into Uver adenine, llie DCM was found to be less active in promoting the incorporation, and this effect could be correlated with its toxicity relative to amethopterin. 

Resistance to End Product Repression, a) Antimetabolites. The use of toxic antimetabolites to select resistant cultures often yields mutants whose normal biosynthetic pathway enzymes are not repressed by the end product. For example, trifluoreoleucine selects mutants with derepressed levels (as much as 10-fold) of leucine biosynthetic enzymes (Calvo and Calvo, 1967). Certain canavanine-resistant mutants produce 30 times more of the arginine pathway enzymes than do their sensitive parents (Jacoby and Gorini, 1967). Mutants of Lactobacillus casei resistant to dichloroamethopterin are derepressed 80-fold in their ability to form thymidylate synthetase (Crusberg and Kisliuk, 1969). When Diplococcus pneumoniae mutants are selected on the basis of resistance to amethopterin, these cultures produce 100 times as much dihydrofolate reductase as the parent culture (Sirotnak et al, 1969). 

Aminopterin 4-amino-4-deoxyfolic acid (see Vitamins, folic acid), a cytostatic agent used in the management of some caneers. It inhibits the enzyme dihy-drofolate reductase, which reduces the folate coenzymes required for Purine biosynthesis (see) and thymine production (see Pyrimidine biosynth is), and thus prevents DNA synthesis However, it is toxic to nondividing cells as well, and cannot be tolerated indefinitely. Methotrexate (amethopterin) has similar activity. 

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