Anticancer agent — R-115777
Advances in cancer treatment have led to significantly improved life expectancies in patients suffering from many different cancers, and some are completely treatable if they are caught early .
Anticancer drugs work through many different mechanisms, and optimising the balance between their cytotoxic effects in cancer cells against their general toxicity can be difficult. One route to cancer treatment that has been receiving much attention is interrupting the action of small membrane-bound G-proteins. These are an essential part of signal transduction and cellular transformation, through their interactions with membrane receptors. Of these proteins, the Ras proteins have been the focus for groups developing potential anticancer drugs because oncogenic mutations have been found in around a third of all human malignancies.
An essential part of the maturation of Ras proteins into their membrane-bound form is farnesylation, catalysed by the enzyme farnesyl protein transferase. Inhibiting this process would lead to potential anticancer agents, and several such drugs are in clinical trials. One of these, R-115777, is being developed by Janssen Pharmaceutica in Belgium. The non-peptide methylquinolone derivative is orally bioavailable, and has been shown to be active both in vitro and in vivo.
In a Phase II trial, 39 patients suffering from advanced breast cancer were given the drug orally twice a day. After three months, 10 of the patients' disease had stabilised, and three were still stable after six months. The drug was well tolerated, with the most commonly seen side-effects being myelosuppression and numbness.1
The drug is undergoing Phase I and Phase II trials against a range of different malignancies, and Phase III trials in pancreatic cancer. Phase I trials include investigations into its use in combination with other anticancer agents, including gemcitabine,2 capecitabine3 and 5-fluorouracil with leucovorin.4