C-1027, A Radiomimetic Enediyne Anticancer Drug, Preferentially Targets Hypoxic Cells

Abstract

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.

Lidamycin inhibits tumor growth and pulmonary metastasis in murine breast carcinoma and shows synergy with paclitaxel

“…LDM (C1027) also showed antiangiogenesis and antimetastatic activity, preferentially targeting hypoxic cells [14]. In the previous study, it has been studied for cancer treatment, enhancement of its targeting, selectivity and efficiency, and drug combination therapy of certain cancers [33][34][35].…”

“…LDM also markedly inhibits the growth of transplantable tumors in vivo [11][12][13]. LDM has demonstrated unique characteristics in the treatment of cancer, such as preferentially targeting hypoxic cells, dosage-dependent regimens based upon p53 status, and high activity against multidrug-resistant cancer cells [14][15][16]. LDM is now in phase II clinical trials as a potential chemotherapeutic agent in China.…”

Antitumor effects of an engineered and energized fusion protein consisting of an anti-CD20 scFv fragment and lidamycin

“…In addition, the hypoxic nature of cells within solid tumors limits the efficacy of anticancer therapies, such as ionizing radiation and conventional radiomimetics, because their mechanisms of action require oxygen to induce lethal DNA breaks. Terry et al [30] reported that LDM could preferentially target hypoxic cells within tumors and overcome the radioresistance associated with poorly oxygenated cells. Therefore, anti-CD20 scFv-LDP-AE has the potential to overcome both the RTX-resistance and the radioresistance associated with poorly oxygenated cells in the treatment of B-cell NHL.…”

DNA Interstrand Cross-Linking Agents and their Chemotherapeutic Potential

“…A recent study reported that treatment with C-1027 (Fig. 31) offers a facile approach for overcoming the radioresistance associated with poorly oxygenated cells [54].…”