DTIC: Towards an Appropriate Alternative
As a result of relatively poor patient tolerance, considerable effort has been made over the past decade in the search for a suitable second-generation clinical alternative to 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide (DTIC, Dacarbazine). Our own investigations have produced an extensive structure-activity series of photostable aryltriazenes. From this study we have concluded that the necessary requirements for antitumour activity in this class of compounds are a carrying group (aryl or heterocyclic) at N1 and a methyl group at N3, together with a readily metabolisable group also at N3. Triazenes of this type undergo hepatic oxidative metabolism to produce a cytotoxic monomethyltriazene. Selected examples of these compounds have been tested against a number of human tumour xenografts. In the U.S.A., the National Cancer Institute has demonostrated that compounds such as 1-(4-carbamoylphenyl)-3-ethyl-3-methyltriazene (CB 10-335) have marked activity against colon and lung tumour xenografts. Perhaps of more interest is the activity towards Grade IV astrocytoma xenografts. Subcutaneous implants of such tumours are sensitive to both DTIC and 1-(4-carbamoylphenyl)-3-methyl-3- pentyltriazene (CB 10-350) but an intracerebral implant is sensitive only to CB 10-350. Experimental antitumour activity is not the sole criterion in selecting a drug for Phase I clinical trial. Highly lipophilic molecules such as the 4-carbamoylphenyltriazenes, whilst necessary for penetration of the blood brain barrier, are difficult to formulate. Recent studies with DTIC suggest that human liver may be incapable of sufficient activation of the dialkyltriazenes by oxidative metabolism. Rather an alternative prodrug may be required.