Resistance to cytotoxic and anti-angiogenic anticancer agents: similarities and differences.
Intrinsic resistance to anticancer drugs, or resistance developed during chemotherapy, remains a major obstacle to successful treatment. This is the case both for resistance to cytotoxic agents, directed at malignant cells, and for resistance to anti-angiogenic agents, directed at non-malignant endothelial cells. In this review, we will discuss mechanisms of resistance which have a bearing on both these conceptually different classes of drugs. The complexity of drug resistance, involving drug transporters, such as P-glycoprotein, as well as resistance related to the tissue structure of solid tumors and its consequences for drug delivery is discussed. Possible mechanisms of resistance to endothelial cell-targeted drugs, including inhibitors of the VEGF receptor and EGF receptor family, are reviewed. The resistance of cancer cells as well as endothelial cells related to anti-apoptotic signaling events initiated by cell integrin-matrix interactions is discussed. Current strategies to overcome resistance mechanisms are summarized; they include high-dose chemotherapy, tumor targeting of cytotoxics to improve tumor uptake, low-dose protracted (metronomic) chemotherapy and combinations of classical agents with anti-angiogenic agents. This review discusses primarily literature published in 2001 and 2002.
Broxterman
Henk J
HJ
Department of Medical Oncology, VU University Medical Center, BR 232, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. H.Broxterman@Vumc.nl
Lankelma
Jan
J
Hoekman
Klaas
K
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents