Amino acid degrading enzymes for cancer therapy.
The development of microbial enzymes for cancer therapy presents difficulties not commonly experienced with biological drugs. The development of the enzyme asparaginase from Escherichia coli in the USA and of the serologically different asparaginase from the plant pathogen Erwinia carotovora in this Establishment, has not only added to the choice of antileukaemia drugs but also provided a valuable guide to the selection and development of new therapeutic enzymes. Our own programme has led to the study of enzymes that degrade other amino acids (glutamine, arginine, phenylalanine and tyrosine) that appear to be important to certain leukaemia cells. Microbes with only remote associations with man were considered as a source of these to minimize initial immunological sensitivity. In the case of erwinia asparaginase the benefits of this have probably included a lower incidence of anaphylaxis compared with the escherichia enzyme. The selection of a stable, high-affinity enzyme that operates efficiently under physiological conditions ensures effective depletion of a circulating amino acid but the choice is very limited. It is also difficult to assess from laboratory tests the likely persistence, toxicity and efficacy of the enzyme in clinical use and to arrive at meaningful biological tests for the quality control of the finished product. Some of the difficulties will be described and proposals made for criteria of acceptance for this type of drug in experimental use.
D000421:Alcaligenes / Q000201:enzymology; D000818:Animals; D001215:Asparaginase / Q000009:adverse effects / Q000627:therapeutic use*; D004285:Dogs; D004885:Erwinia / Q000201:enzymology; D004926:Escherichia coli / Q000201:enzymology; D005972:Glutaminase / Q000627:therapeutic use*; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy*; D011817:Rabbits; D051381:Rats
D001215:Asparaginase; D005972:Glutaminase