The need for additional alkylating agents and antimetabolites.

The title that was assigned to me is a clear invitation to pontificate. Instead, I will share with you a few modest and not very original thoughts and speculations. These are based on a large literature and a small experience of tilling the soil among certain obscure and unnatural pyrimidines. This engage ment with the rationality of antimetabolites followed an ignoble exodus from the quagmire surrounding an even more obscure alkylating agent. Thus, my bias is already exposed. It is not my purpose to cover the enormous literature in these two fields of alkylating agents and antimetabolites. Rather, I shall refer to reviews whenever possible. Nor do I intend to explore systematically structure-activity relation ships of every series of compounds, detailed screening results, comparative toxicology, clinical pharmacology, and mechanisms of action. I will try merely to focus on certain facts, trends, and promising leads that happen to interest me and suggest points of departure for future synthetic chemical forays. I shall emphasize drug design at the expense of ignoring the exciting advances in cell-cycle kinetics and clinical com bination chemotherapy that have been emphasized elsewhere in this Symposium. I shall forbear from intoning the custom ary litany of our ignorance of the essential molecular lesions of malignancy and intend to proceed with what is known. But I had better proceed.