264 1. lODOACETATE AND lODOACETAMIDE 



the tumors. Selle and Bodansky (1935) reasoned that bromoacetate might 

 not penetrate into the tumors and hence tried bromocaproate injected in 

 oHve oil subcutaneously, but found no inhibition of rat Sarcoma 39, which 

 is not surprising since bromocaproate is, as far as one knows, not a good 

 glycolytic inhibitor. 



lodoacetate injected intraperitoneaUy into rats bearing Tumor 256 at a 

 dose of 7 mg/kg/day causes some reduction in over-all growth rate of the 

 animals and also some retardation of tumor growth, but apparently little 

 selectivity is evident (Brunschwig et al., 1946). lodoacetamide administered 

 in the same manner to mice bearing Sarcoma 37 causes some regression 

 or retardation of tumor growth, this being particularly significant when the 

 tumors are initially large, untreated tumors weighing 3.7 times as much 

 as the tumors in treated animals (Friedman and Rutenberg, 1950 b). Sum- 

 marizing all the results, one might conclude that a degree of selectivity 

 may be attained with certain types of tumor, although appreciable regres- 

 sion of the tumors is usually seen only when some toxicity also occurs. 

 Although these limited observations with iodoacetate are not especially en- 

 couraging, quite possibly specific tumors might respond well enough so that 

 the use of iodoacetate, at least in conjunction with other carcinostatic agents 

 might be entertained. One must remember that low doses of iodoacetate 

 may possibly stimulate tumor growth, since this seems to be a characteristic 

 of this type of inhibitor, so that intensive therapy is indicated. 



The only clinical test of iodoacetate was reasonably encouraging (Black 

 and Kleiner, 1947; Black et al., 1947). Given to patients at a dosage of 60- 

 90 mg/day orally (which one may note is around 1 mg/kg/day and a dosage 

 much lower than in experimental animals), it exert suppressive effects on 

 lymphosarcoma, myeloblastic leukemia, carcinoma liver metastases, and 

 other neoplasms. In a number of cases there is hematological remission for 

 several months, or a shrinkage in tumor mass with relief from pain and 

 general weight gain. However, as is the case with most carcinostatic agents, 

 tolerance develops and the tumor escapes. Nevertheless, these results seem 

 to justify further work, especially using iodoacetate in combination ther- 

 apy rather than sequentially. 



Various interesting bifunctional derivatives of iodoacetate and lodoacet- 

 amide were synthesized and tested by Kramer et al. (1963), on the basis 

 that they are highly active alkylating agents and might be cross-linking. 

 A typical compound is ethylenebis (iodoacetate): 



I— CH^— CO— O— CH2CH2— O— CO— CH^— I, 



which hydrolyzes slowly in physiological media (half-life of 80 min in phos- 

 phate buffer at pH 7.4 and 37°) but more rapidly in serum or tissue ex- 

 tracts. The enzymic and metabolic effects of such compounds are unknown, 

 but the compound above (known as S-10) is 4-8 times as toxic as iodoace- 



