Multilevel therapeutic targeting by topoisomerase inhibitors.
The successful use of cytotoxic agents in the clinical management of LCH depends upon the selective targeting of cells participating in the disease process. The topoisomerase 'poisons', currently used extensively in the treatment of aggressive malignancies, represent an intriguing class of cytotoxic agents exerting their cytostatic and cytotoxic effects at multiple levels according to cell type. The non-DNA intercalating topoisomerase II poison, etoposide (VP-16), is the "drug of first choice" in the treatment of LCH by cytotoxic chemotherapy. This major anticancer agent traps the nuclear enzyme DNA topoisomerase II on DNA in a sequence-specific manner, the processing of trapped complexes giving rise to a plethora of cellular effects not least the potential activation of pathways leading to cell cycle arrest and apoptosis. This short review describes the principles of topoisomerase inhibition, the multiplicity of cellular effects and the concept of cellular targeting in LCH. The successful treatment of LCH by cytotoxic chemotherapy will depend on both the identity of the target tissues and a clear view of therapeutic intent, given the potential for induction of haematological neoplasia.
Smith
P J
PJ
MRC Clinical Oncology and Radiotherapeutics Unit, MRC Centre, Cambridge, England.
Souès
S
S
D000970:Antineoplastic Agents / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000187:drug effects / Q000502:physiology; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000502:physiology; D005047:Etoposide / Q000494:pharmacology; D006646:Histiocytosis, Langerhans-Cell / Q000188:drug therapy*; D006801:Humans; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II