Is gamma-linolenic acid an effective intravesical agent for superficial bladder cancer? In vitro cytotoxicity and in vivo tolerance studies.

Abstract

The essential fatty acid gamma-linolenic acid (GLA) is an effective cytotoxic agent when applied topically and for prolonged periods to tumour cells. Topical application, by intravesical therapy, is firmly established in the treatment of superficial bladder cancer. However, this form of therapy is limited to a maximum duration of 2 h. At such a short drug exposure time, does GLA retain its cytotoxicity? We have examined this question by exposing the superficial bladder cancer cell lines MGH-U1 and RT112 to meglumine-GLA (MeGLA) for time intervals ranging from 30 min to 2 h, at drug concentrations ranging from 1000 to 1.95 microg/ml. The MTT viable biomass assay was used to assess cell kill. Greater than 90% inhibition was observed at a concentration of 125 microg/ml (IC > 90), at 2 h drug exposure. At shorter drug exposure times, higher drug concentrations were needed to induce the same effect. At 1 h drug exposure, the IC > 90 was recorded at 500 microg/ml. In vivo intravesical tolerance studies were conducted in rats. Rats exposed to 2.5 mg/ml MeGLA intravesically for 2 h or less remained well and bladder histology showed minimal changes. This study confirms that GLA retains its cytotoxicity at short drug exposure times and is well tolerated by normal bladder mucosa in vivo. Bladder mucosa tolerated > 10x the concentration required for the IC > 90 in vitro. MeGLA is therefore a feasible intravesical agent for superficial bladder cancer.