C-1027, a radiomimetic enediyne anticancer drug, preferentially targets hypoxic cells.
The hypoxic nature of cells within solid tumors limits the efficacy of anticancer therapies such as ionizing radiation and conventional radiomimetics because their mechanisms require oxygen to induce lethal DNA breaks. For example, the conventional radiomimetic enediyne neocarzinostatin is 4-fold less cytotoxic to cells maintained in low oxygen (hypoxic) compared with normoxic conditions. By contrast, the enediyne C-1027 was nearly 3-fold more cytotoxic to hypoxic than to normoxic cells. Like other radiomimetics, C-1027 induced DNA breaks to a lesser extent in cell-free, or cellular hypoxic, compared with normoxic environments. However, the unique DNA interstrand cross-linking ability of C-1027 was markedly enhanced under the same hypoxic conditions that reduced its DNA break induction. Although the unique chemistry of C-1027 allows it to concurrently generate both DNA breaks and cross-links in normoxic cells, a low oxygen environment represses the former and promotes the latter. Thus, treatment with C-1027 offers a facile approach for overcoming the radioresistance associated with poorly oxygenated cells.
Beerman
Terry A
TA
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA. Terry.Beerman@roswellpark.edu
Gawron
Loretta S
LS
Shin
Seulkih
S
Shen
Ben
B
McHugh
Mary M
MM
D000617:Aminoglycosides / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004249:DNA Damage; D004278:DNA, Superhelical / Q000187:drug effects; D053281:Enediynes / Q000494:pharmacology*; D045325:HCT116 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D010100:Oxygen / Q000378:metabolism; D010957:Plasmids / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects
D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D004278:DNA, Superhelical; D053281:Enediynes; C468783:H2AX protein, human; D006657:Histones; C058024:C 1027; D010100:Oxygen