Progress and perspectives of systemic anticancer treatment

Cancer chemotherapy embodies an expanding breadth of molecular and biological disciplines and is evolving from approaches based solely on DNA synthesis to include approaches based on a vast number of cellular factors that may differ between malignant and normal tissues. These factors include response to growth factors, antigenic determinants on cell membranes, the ability to respond to signals of differentiation and/or proliferation, and the ability to stimulate cytotoxic recognition responses. Concurrently, the use of agents designed to interfere with DNA synthesis has led to a better understanding of the molecular events that cause drug resistance. The use of these drugs demonstrated that mechanisms operating in antimetabolite resistance may be quite different from those operating in resistance to alkylating agents. Further, multiple changes may frequently coexist in the same cells. Conceptual advances in the area of drug resistance continue to support the long-held concept that the probability of cure is greatest when the tumor burden is small. National Cancer Institute efforts in drug discovery are now designed to explore these recent developments using screening systems that employ human tumors that are usually resistant to therapy. This approach is expected to contribute substantially to the ability to cure malignant disease.