Abstract
2,3,5-Trimethyl-6-(3-pyridylmethyl) 1,4-benzoquinone (CV-6504), an inhibitor of 5-lipoxygenase, effectively suppressed growth of the MAC16 tumour in vivo and prevented the accompanying cachexia, when administered daily at a dose of 10 mg kg(-1). There was a reduction in the tumour concentration of linoleic (LA), arachidonic (AA), oleic, stearic and palmitic acid. In order to elucidate the mechanism of the anti-tumour action, the effect of CV-6504 on the metabolism of AA through the 5-, 12- and 15-lipoxygenase pathways has been determined in cell lines sensitive (MAC16, MAC13, MAC26 and Caco-2) and resistant (A549 and DU-145) to CV-6504. Incubation of all cell lines with [3H]AA led to the appearance of [3H]5-, 12- and 15-HETE. Preincubation of MAC16, MAC13, MAC26 and Caco-2 with 10 microM CV-6504 inhibited the conversion of AA to 5-, 12- and 15-HETE, while in A549 and DU-145 cells there was no effect on metabolism through any lipoxygenase pathway. Two other cell lines, MDA-MB-231 and PC-3, sensitive to growth inhibition by CV-6504, are known to require LA for growth, while DU-145, which was insensitive to growth inhibition by CV-6504, showed no growth response to LA. These results suggest that some tumours are dependent on lipoxygenase metabolites of LA and AA for their continual growth, and interference with this pathway produces a specific growth inhibition.
Highlights
6504 inhibited the conversion of arachidonic acid (AA) to 5, 12- and 15-hydroxyeicosatetraenoic acids (HETE), while in A549 and DU-145 cells there was no effect on metabolism through any lipoxygenase pathway
Anti-tumour activity was reduced by concomitant administration of linoleic acid (LA), suggesting that the anti-tumour effect may be mediated through inhibition of the metabolism of this polyunsaturated fatty acid (PUFA)
Growth of the MAC 16 tumour in NMRI mice is accompanied by a progressive cachexia, which increases as tumour growth increases (Beck and Tisdale, 1987)
Summary
6504 inhibited the conversion of AA to 5-, 12- and 15-HETE, while in A549 and DU-145 cells there was no effect on metabolism through any lipoxygenase pathway. We have recently shown CV-6504 to exert profound anti-tumour activity against three murine adenocarcinomas (MAC16, MAC13 and MAC26), which are generally refractory to cytotoxic agents (Hussey et al, 1996) This compound is to undergo clinical evaluation against pancreatic carcinoma. PUFAs, and LA in particular, have been implicated as tumour promoters (Reddy and Masura, 1984), as enhancers of metastasis (Rose et al, 1991) and as stimulators of tumour growth in vitro (Wicha et al, 1979) and in vivo (Hussey and Tisdale, 1994) These effects are probably due to metabolism of LA to prostaglandins or products of the lipoxygenase pathways. 12-HETE has been suggested as an important determinant of the metastatic potential of tumour cells (Liu et al, 1994) These results suggest that CV-6504 may exert its anti-tumour activity as a result of the inhibition of a lipoxygenase pathway. The effect of CV-6504 on the lipoxygenase pathways of cell lines with varying sensitivity to growth inhibition by this agent has been evaluated
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