Subject(s)
Antineoplastic Agents/administration & dosage , Hutchinson's Melanotic Freckle/drug therapy , Imiquimod/administration & dosage , Skin Neoplasms/drug therapy , Administration, Cutaneous , Aged, 80 and over , Antineoplastic Agents/adverse effects , Drug Administration Schedule , Female , Humans , Hutchinson's Melanotic Freckle/pathology , Imiquimod/adverse effects , Skin Neoplasms/pathology , Time Factors , Treatment OutcomeSubject(s)
Antimetabolites, Antineoplastic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Fluorouracil/adverse effects , Leucovorin/adverse effects , Vasculitis, Leukocytoclastic, Cutaneous/chemically induced , Vitamin B Complex/adverse effects , Aged , Colorectal Neoplasms/drug therapy , Humans , MaleABSTRACT
The synthesis of new conformationally biased cyclic pentapeptides, incorporating the RGD sequence, and built around a tetrahydroazoninone scaffold, is reported. They exhibit interesting activity towards integrin alphaVbeta3 and a remarkable selectivity in comparison with integrin alphaVbeta5.
Subject(s)
Azo Compounds/chemical synthesis , Integrins/metabolism , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/pharmacology , Azo Compounds/pharmacology , Humans , Integrin alphaVbeta3/metabolism , Ligands , Molecular Conformation , Oligopeptides , Receptors, Vitronectin/metabolism , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Anticancer agents that interfere with microtubulin function are in widespread use in man and have a broad spectrum of activity against both hematological malignancies and solid tumors. The mechanisms of actions of these agents have been better defined during the past decade, indicating that there are distinct binding sites for these agents and that they interfere with microtubulin dynamics (growth and shortening of tubules) at low concentrations and only evoke microtubulin aggregation or dissociation at high concentrations. Tubulin has been recently described in the nucleus of cells and in mitochondria. Downstream events from tubulin binding are believed to be critical events for the generation of apoptosis in the malignant cell. The effects of vinca alkaloids and taxanes are distinct, suggesting that the interference with the tubulin cap by high-affinity binding of effective agents is not the only mechanism of cytotoxic effect, and the low-affinity binding of drug, which distorts microtubulin function, may also be important. The epothilones share some of the binding characteristics of the taxanes and are in clinical trials because of cytoxic activity in taxane resistant cells. Tubulin has additional target sites for anticancer drugs including interference with the binding and function of microtubule associated proteins and interference with motor proteins which are essential for the transport of substances within the cell. Because many of these microtubule associated proteins have an ATP binding site, both computer-aided design and combinatorial chemistry techniques can be used to make agents to interfere with their function analogous to imatinib mesylate (Gleevec). Agents that interfere with the motor protein kinesin are entering clinical trials.
