Benjamin Witten

Preliminary study of an esterase-susceptible water-soluble agent (S-73) for regional chemotherapy

This is a preliminary report on the experimental and clinical use of a new alkylating agent (S‐73) which is water soluble, stable to hydrolysis for hours, but with esterase‐susceptible linkages, which results in inactivation of the agent by esterase in the blood. S‐73 is a potent cytotoxic agent when injected near its target but much larger doses are required to produce cytotoxic effects when injected farther away from it, because of rapid inactivation and dilution. In no instance is bone marrow depressed.

Enzyme alterable alkylating agents X: Experimental study of an esterase-susceptible water-soluble agent (S-73) for Regional Chemotherapy☆

Abstract Although circumvention of the problem of systemic toxicity during regional infusions was shown to be possible with S-182, an alkylating agent with a very short half-life, practical use of this drug was hampered by its lack of water solubility and damage to normal tissue near the injection site. Studies were undertaken to find an agent without such shortcomings and ethylene N-2-chloroethyl-N-methylglycine, diester (S-73), a stable water-soluble, bifunctional alkylating agent with esterase-susceptible bonds was studied further. This compound should be rapidly detoxified by esterases in blood and epithelial tissue. In dogs, low doses of S-73 (0.27 μm./kg.) injected into a branch of the mesenteric artery, about 10 cm. from the intestine, damaged the intestinal epithelium but no damage occurred when injected 20 cm. away. HN2 (0.06 μm./kg.) unlike S-73, did not lose its cytotoxic effect when injected twice as far from its target. High doses of S-192 (a monofunctional mustard which could result from the cleavage of S-73 by esterase) were innocuous when injected 10 cm. from the intestine. Bone marrow depression occurred only with high doses of S-73 (17.6 μm./kg.) injected into the left ventricle but not through the femoral vein. The significance of this observation is enhanced by the observation that 2.6 μm. per kilogram of HN2 by either route depresses bone marrow. In vitro studies, however, show that S-73 is not rapidly detoxified in blood, and suggest that much of the compound may be in the uncyclized form which is incapable of alkylating at the time it reaches the target. Nevertheless, in vivo studies reveal that considerable alkylation has occurred at the target. Furthermore, rapid detoxification of S-73 may be inferred by the higher doses required to effect regional damage, the relationship of its cytotoxic effect to distance from the target, and the lack of local effect of its presumed metabolite. Since very high doses of S-192 caused damage in the lungs of dogs, it is not surprising that equivalently high doses of S-73 are also damaging to lung. Preliminary clinical trials [2] in advanced cancer patients have shown that high doses of S-73 have not produced damage to either bone marrow or lung. Mucosal damage on intramesenteric arterial injection and spinal cord damage via the lower aorta in dogs as well as preliminary clinical observations have shown that S-73 is a potent cytotoxic agent when injected near a limited target. On the other hand high doses in a larger tumor-bearing area produced minimal damage to local tissue with no significant systemic effects. Whether clinical cancer can be specifically and significantly damaged with this new agent is in the process of investigation.

Enzyme alterable alkylating agents. XI. Clinical trials of an esterase-susceptible water-soluble agent (S-73) for regional chemotherapy

Abstract Clinical trials of a new water-soluble short half-life alkylating agent (S-73) administered by intra-arterial infusion into 56 patients with a variety of malignant tumors, revealed only limited usefulness. The best responses were seen in a case of Kaposis sarcoma, a squamous cell carcinoma of the tongue, an epidermoid carcinoma of the cervix, and metastatic carcinoid to liver. In all, there were 5 good responses, 3 fair responses, 36 with no response, and 12 indeterminates. Further modifications in design and structure of S-73 are in progress to probe for greater tumor specificity.