Richard P. Bryce

Essential fatty acids: molecular and cellular basis of their anti-cancer action and clinical implications

3. EFA cytoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 3.1. Cytotoxic effects of EFAs on cancer cells . . . . . . . . . . . . . . . . . . . . . . . . . . . 182 3.2. Cytoxicity dependence on peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 3.2.1. EFA-converting deficiency of cancer cells . . . . . . . . . . . . . . . . . . . . . . . 185 3.2.2. Lipid peroxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 3.3. EFAs and apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 3.4. Cytokine dependent cell growth regulation . . . . . . . . . . . . . . . . . . . . . . . . . . 186 3.5. EFAs, chemotherapy and radiation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186 3.5.1. Enhancement of sensitivity and reversal of cytotoxic drug resistance by EFAs. . 186 3.5.2. EFAs sensitise tumour cells to radiation . . . . . . . . . . . . . . . . . . . . . . . . 186 3.6. Regulation of gene and oncogene expression by EFAs . . . . . . . . . . . . . . . . . . . 186

Gamma linolenic acid with tamoxifen as primary therapy in breast cancer

Gamma linolenic acid (GLA) has been proposed as a valuable new cancer therapy having selective anti‐tumour properties with negligible systemic toxicity. Proposed mechanisms of action include modulation of steroid hormone receptors. We have investigated the effects of GLA with primary hormone therapy in an endocrine‐sensitive cancer. Thirty‐eight breast cancer patients (20 elderly Stage I‐II, 14 locally advanced, 4 metastatic) took 8 capsules of oral GLA/day (total = 2.8 g) in addition to tamoxifen 20 mg od (T+GLA). Quality and duration of response were compared with matched controls receiving tamoxifen 20 mg od alone (n = 47). Serial tumour biopsies were taken to assess changes in oestrogen receptor (ER) and bcl‐2 expression during treatment. GLA was well tolerated with no major side effects. T+GLA cases achieved a significantly faster clinical response (objective response vs. static disease) than tamoxifen controls, evident by 6 weeks on treatment (p = 0.010). There was significant reduction in ER expression in both treatment arms with T+GLA objective responders sustaining greater ER fall than tamoxifen counterparts (6‐week biopsy p = 0.026; 6‐month biopsy p = 0.019). We propose GLA as a useful adjunct to primary tamoxifen in endocrine‐sensitive breast cancer. The effects of GLA on ER function and the apparent enhancement of tamoxifen‐induced ER down‐regulation by GLA require further investigation. Int. J. Cancer 85:643–648, 2000.

Effect of dietary GLA+/−tamoxifen on the growth, ER expression and fatty acid profile of ER positive human breast cancer xenografts

Gamma linolenic acid (GLA) possesses a number of selective anti‐tumour properties including modulation of steroid receptor structure and function. We have investigated the effect of dietary GLA on the growth, oestrogen receptor (ER) expression and fatty acid profile of ER+ve human breast cancer xenografts. Experimental diets A, B, C, D were commenced after subcutaneous implantation of 40 female nude mice with the MCF‐7 B1M cell line (Group A = control diet: B = control diet + GLA supplement: C = control diet + tamoxifen: D = control diet + GLA + tamoxifen; 10 mice/group). The mice were terminated when tumour cross‐sectional area reached 250 mm2. ER H‐scores were assessed by immunohistochemical assay and fatty acid profiles by gas‐liquid chromatography of termination tumour samples. Groups C and D displayed significantly slower tumour growth (p =.0002, p =.0006) with trend for slower growth in B (p =.065) compared to control Group A. ER was significantly reduced in all groups compared to A (p <.0001) with Group D (combined therapy) displaying markedly lower ER expression than with either therapy alone (p =.0002). There were significantly raised levels of tumour GLA and metabolites in the two groups (B and D) receiving GLA (p <.0001). This xenograft model of ER+ve breast cancer has demonstrated significantly lower tumour ER expression in those groups receiving GLA, an effect which appears to be additive to the reduced ER expression resulting from tamoxifen alone. The effects of GLA on ER function and the possibility of synergistic inhibitory action of GLA with tamoxifen via enhanced down‐regulation of the ER pathway require further investigation.

Gamma linolenic acid regulates gap junction communication in endothelial cells and their interaction with tumour cells

Tumour-endothelial cell adhesion forms a key role in the establishment of distant metastases. This study examined the effect of gamma linolenic acid (GLA), an anti-cancer polyunsaturated fatty acid (PUFA), on both the gap junction communication of human vascular endothelial cells and tumour cell-endothelial interactions. By using scrape loading of Lucifer yellow dye, we showed that GLA at non-toxic levels increased Lucifer yellow transfer, indicating improved gap junction communication. The fatty acid also corrected the communication that was reduced by the mitogenic and motogenic factor HGF/SF. GLA inhibited the tyrosine phosphorylation of connexin-43, a protein that formed gap junction in this cell. When human tumour cells were added to quiescent or HGF/SF-activated endothelial cells, the presence of GLA reduced adhesion of tumour cells to the endothelium. It is concluded that GLA reduces tumour-endothelium adhesion, partly by improved gap junction communications of the endothelium.