Anticancer agent - MKC-1
Interrupting the cell cycle process is an important strategy in treating cancer, and some drugs are able to hit multiple pathways, making resistance less likely.
Interrupting the cell cycle process is an important strategy in treating cancer, and some drugs are able to hit multiple pathways, making resistance less likely.
MKC-1, formerly known as Ro-31-7453, is a novel cell cycle inhibitor that is orally active, and it appears to work by arresting cellular mitosis and inducing apoptosis by binding to a number of cellular proteins, including tubulin and members of the importin β family.1 It also inhibits activation of the oncogenic kinase Akt and the mTOR pathway, but the mechanism of this is as yet unknown. It is being developed by US company EntreMed, which licensed it from Roche, as a potential treatment for a number of different cancer types.
Several clinical trials have been carried out, including an open label Phase I/II trial in combination with pemetrexed in patients with advanced non-small cell lung cancer.2 In the Phase I dose finding part of the study, subjects were given 75mg/m2 of the new drug, and 500mg/m2 of pemetrexed, and no dose limiting toxicities were observed. The main side-effects observed were fatigue, nausea, anorexia, vomiting and dyspnea. In the Phase II part, seven of the 11 subjects were evaluable for tumour response, and all seven achieved stable disease. One of these, whose disease had progressed following two earlier chemotherapy regimens, exhibited stable disease for more than eight months, and when the results were published was still taking MKC-1 as monotherapy.
It has also been investigated as a treatment for breast cancer. In a Phase II trial, 58 patients with metastatic breast cancer who had previously been treated with a taxane and an anthracycline were given the drug in doses of 125mg/m2 twice a day for the first 14 days of a 28 day cycle.3 The dose was adjusted based on neutropoenia occurrence in the first cycle - 51% had the dose increased for the second cycle, and 11% were given reduced doses. Five patients discontinued because of toxicity, but it was well tolerated, and grade 3 drug-related toxicities included elevated AST/ALT, neutropoenia, mucositis and sensory neuropathy. One patient died from neutropoenic sepsis. Of the 49 patients who were evaluable for response, three had an objective response, and a further seven achieved stable disease.