Anticancer agent - TLK-286

The unspecific nature of many chemotherapy drugs means that the side-effects are frequently unpleasant, and can be treatment limiting.

If drugs could be designed to be specific for tumour cells, then there is likely to be less collateral damage and the drugs would be more efficacious.

US biotech Telik is investigating cancer cell activated chemotherapeutics, and its most advanced product, TLK-286, was designed to exploit the overexpression of the detoxification enzyme glutathione S-transferase P1-1 (GST P1-1), an enzyme that is overexpressed in many human cancer cells.¹ High levels of GST P1-1 are associated with a poor prognosis, and resistance to a various chemotherapy drugs.

The company believes its investigational drug is activated when GST P1-1 splits the drug into two active fragments: a glutathione analogue fragment, and an active cytotoxic fragment that reacts with cell components including DNA and RNA, leading to cell death. It also believes that the glutathione fragment may remain bound to GST P1-1, which may limit its ability to inactivate other drugs, providing a synergistic effect with other drugs.

A number of trials have been carried out in ovarian, non-small cell lung, breast and colorectal cancers. A Phase II trial was run in 36 patients with ovarian cancer that was refractory or resistant to paclitaxel or platinum drugs.² Around half of the patients had also failed at least one salvage therapy. Subjects were given 1000 mg/m² of TLK-286 once every three weeks. A complete response was observed in one patient, partial responses in four patients, and a further 12 achieved stable disease. The median survival of the responders was 19.5 months, and progression-free survival for the same group was 7.1 months. Both of these figures were greater than would be expected in such a heavily pre-treated population.

Another Phase II trial was carried out in patients with non-small cell lung cancer who had failed platinum-based chemotherapy.³ A total of 52 patients, more than half of whom had failed third-line salvage therapy, were given 1000 mg/m² of TLK-286 every three weeks. Of the 41 patients who were evaluable for response at interim analysis, 21 had achieved stable disease.

It has also been investigated in 73 patients with refractory colorectal cancer who had failed therapy with 5-fluorouracil, irinotecan and luecovorin.⁴ At interim analysis, of the 36 evaluable for response five had achieved stable disease, and the estimated median survival was 172 days. The drug is also being investigated in combination with other chemotherapeutic agents.