New leads in cancer therapeutics: A keynote address

The main problems in cancer chemotherapy are related to the fact that the a vailable drugs are not specific nor selective enough in their anticancer ac tion. 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 to xicity. 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 traditiona l approaches of drug discovery stemming from lead chemical structures and i n many cases utilizing combinational chemistry followed by suitable screeni ng efforts; 2) Increasing the antitumor effectiveness of available drugs th rough: a) making It possible to Increase drug dose intensity by protecting normal tissues from limiting toxicity through genetic manipulation or combi nation with such agents as GM-CSF or IL15; b) attempting to increase the sp ecificity of drug delivery through the administration of agents encapsulate d in suitable liposome or conjugated with appropriate antibodies or cytokin es; c) increasing the sensitivity of target tumor to a drug by specific met abolic 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 examp le, mechanisms of drug uptake or retention or at reducing anti-apoptotic me chanisms; 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 relationshi ps; 5) continuing efforts to develop more effective and selective combinati on treatments with drugs, biologicals or different modalities; and, 6) deve loping new treatments based on intervention at novel molecular targets whic h have an essential role in the physio-pathology of the cancer cell. The la tter approach is the main subject of this address.