Cyclotherapy: protection of normal cells and unshielding of cancer cells.
Avoidance of apoptosis and mitogen-independent growth are hallmarks of cancer. Mitogen-activated kinases (for example, ErbB1, Raf-1, MEK, PI-3-K, mTOR) can suppress chemotherapy-induced apoptosis in cancer cells. While kinase inhibitors restore susceptibility of cancer cells to apoptosis, they do not necessarily cause growth arrest in cancer cells harboring additional mutations in downstream signaling pathways such as inactivation of Rb and overexpression of c-myc. This article provides a conceptual basis for a novel use of inhibitors of mitogenic kinases. While arresting growth of normal cells, kinase inhibitors may not arrest cancer cells but instead can sensitize them to apoptosis. Following pretreatment with low doses of kinase inhibitors, the chemotherapy that predominantly induces apoptosis in cycling cells (cyclotherapy) will kill cancer cells while sparing normal cells.
Blagosklonny
Mikhail V
MV
Laboratory of Translational Oncology, New York Medical College, Hawthorne, New York 10532, USA. M_Blagosklonny@NYMC.EDU
Darzynkiewicz
Zbigniew
Z
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004358:Drug Therapy / Q000379:methods / Q000639:trends; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018816:Genes, cdc / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors