A minimal toxicity approach to cancer therapy: possible role of beta-glucuronidase.
Most cancer cells differ from normal cells in that they show higher beta-glucuronidase activity and lower pH of their cytoplasm. Anti-cancer drugs can be designed which take advantage of these gradients to deliver maximal toxicity to tumors and minimal toxicity to normal tissue. Many design criteria are suggested here, the most basic of which is the use of the glucuronide structure, in which glucuronic acid acts as a protective carrier of a toxic fragment which becomes active when split off by the beta-glucuronidase at the tumor site. The high beta-glucuronidase activity in cancer cells is also discussed here as a possible explanation for some of the pathognomonic features of a malignant growth: the automatic proliferation of tumor tissue, the invasion of tumors into adjacent tissue, the metastases to remote sites, and the weak response of the immune system.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D003593:Cytoplasm / Q000201:enzymology; D004353:Drug Evaluation, Preclinical; D005965:Glucuronates / Q000494:pharmacology / Q000627:therapeutic use*; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure
D000970:Antineoplastic Agents; D005965:Glucuronates; D005966:Glucuronidase