New leads in cancer therapeutics: a keynote address.

The main problems in cancer chemotherapy are related to the fact that the available drugs are not specific nor selective enough in their anticancer action. Therefore, even a low degree of resistance at the target tumor level is sufficient to impart clinical resistance because the dose of drug cannot be increased sufficiently to overcome it without incurring unacceptable toxicity. In the face of the above mentioned difficulties, several directions of research are being currently pursued towards developing more effective and selective treatments of cancer. These include: 1) continuing traditional approaches of drug discovery stemming from lead chemical structures and in many cases utilizing combinational chemistry followed by suitable screening efforts; 2) Increasing the antitumor effectiveness of available drugs through: a) making it possible to increase drug dose intensity by protecting normal tissues from limiting toxicity through genetic manipulation or combination with such agents as GM-CSF or IL15; b) attempting to increase the specificity of drug delivery through the administration of agents encapsulated in suitable liposome or conjugated with appropriate antibodies or cytokines; c) increasing the sensitivity of target tumor to a drug by specific metabolic modulations as it was done, for example, in the case of combinations of fluoropyrimidines with leukovorin; 3) counteracting resistance to drugs through genetic and/or epigenetic approaches aimed at modifying, for example, mechanisms of drug uptake or retention or at reducing anti-apoptotic mechanisms; 4) attempting to improve biotherapeutic treatments, for example, utilizing novel therapeutic vaccines or antibodies, or treatments based on intervention on angiogenesis or on intercellular or cell-matrix relationships; 5) continuing efforts to develop more effective and selective combination treatments with drugs, biologicals or different modalities; and, 6) developing new treatments based on intervention at novel molecular targets which have an essential role in the physio-pathology of the cancer cell. The latter approach is the main subject of this address.