Mechanism of the anti-tumour effect of 2,3,5-trimethyl-6-(3-pyridylmethyl) 1,4-benzoquinone (CV-6504).

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.     

Effect of polyunsaturated fatty acids on the growth of murine colon adenocarcinomas in vitro and in vivo.

The effect of the polyunsaturated fatty acids (PUFAs) linoleic acid (LA) and arachidonic acid (AA) on the growth of two murine colon adenocarcinoma cell lines (MAC26 and MAC13) has been determined both in vitro and in vivo. When the serum concentrations in the medium became growth limiting, low concentrations (18-33 microM) of both PUFAs were growth stimulatory to both cell lines, while higher concentrations were growth inhibitory. Growth stimulation by AA in both cell lines, and by LA in MAC13, was effectively inhibited by both the cyclo-oxygenase and lipoxygenase inhibitor indomethacin, and the lipoxygenase inhibitor BWA4C in a dose-dependent manner. The most effective inhibition was exerted by BWA4C, suggesting metabolism of both PUFAs through the lipoxygenase pathway for growth stimulation. In vivo studies using the MAC26 tumour showed a significant stimulation of tumour growth when LA was administered orally at concentrations higher than 0.4 g kg-1 day-1. Higher concentrations did not produce a further increase in tumour growth rate. This suggests that there is a threshold dose for growth stimulation by LA which, together with that in the diet, amounted to 3.8% of the total caloric intake. The increase in tumour volume induced by LA arose from a reduction in the potential doubling time from 41 to 28 h and was effectively reversed by indomethacin (5 mg kg-1). These results suggest that PUFAs may play an important role in tumour growth and may offer a potential target for the development of chemotherapeutic agents.     

Metabolism and pharmacokinetics of the anti-tumour agent 2,3,5-trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504).

2,3,5-Trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504) is an effective inhibitor of the growth of established murine adenocarcinomas (MACs) and is shortly to enter clinical investigation. When administered to mice bearing the MAC16 tumour, CV-6504 rapidly disappeared from the plasma and tissues and there was an accumulation of the sulphate and glucuronide metabolites. After 24 h, the concentration of free CV-6504 in the tumour (3.3 microM) was higher than that in the liver (0.24 microM) and equal to the IC50 value for the inhibition of the growth of MAC16 cells in vitro (3 microM). The concentration of glucuronide and sulphate metabolites in both tumour and liver decreased with time. Both the MAC16 tumour and the liver possessed similar beta-glucuronidase activity, which could account for the accumulation of free CV-6504. Although the sulphate and glucuronide conjugates of CV-6504 were ineffective inhibitors of the growth of MAC13 cells in vitro at concentrations up to 100 microM, in vivo at a concentration of 50 mg kg-1 day-1 the conjugates produced a similar anti-tumour effect to CV-6504 at a concentration of 5 mg kg-1 day-1. The MAC13 tumour possessed both beta-glucuronidase and sulphatase activity capable of converting the sulphate and glucuronide conjugates to free CV-6504. Using MAC13 cells ex vivo, CV-6504 inhibited conversion of arachidonic acid to 5-, 12- and 15-hydroxyeicosatetraenoic acids (HETE). The percentage reduction in formation of 12- and 15-HETE exceeded that of 5-HETE. Inhibition of HETE formation may be responsible for the anti-tumour activity of CV-6504.     

Inhibition of human malignant neuroblastoma cell DNA synthesis by lipoxygenase metabolites of arachidonic acid

In vivo studies have shown that inhibitors of cyclooxygenase metabolism of arachidonic acid may diminish growth and metastasis of certain tumors. Because cyclooxygenase inhibition may increase the production of lipoxygenase products of arachidonic acid metabolism, we have investigated the effect of two such products, 12-hydroxyeicosatetraenoic acid (12-HETE) and 15-hydroxyeicosatetraenoic acid (15-HETE) on tumor cell proliferation in vitro. When neuroblastoma cells (SK-N-SH) in culture were treated with 12-HETE for 18 hr, incorporation of [3H]thymidine was inhibited up to 64% at concentrations from 20 to 50 microM. Under the same conditions, 15-HETE resulted in inhibition of up to 46%, while arachidonic acid had no apparent effect. When evaluated in the presence of serum, 12-HETE at a concentration of 120 microM produced a 20.6 +/- 2.8% (S.E.) inhibition of the increase in total DNA content over 48 hr, while 15-HETE at this concentration produced a 16.5 +/- 5.3% inhibition. We conclude that 12-HETE, the product of platelet lipoxygenase, and 15-HETE, a product of neutrophil and lymphocyte lipoxygenases, can inhibit human neuroblastoma cell growth in vitro and may play a role in the effect of cyclooxygenase inhibitors on tumor growth in vivo.     

The lipoxygenase metabolite 12(S)-HETE promotes alpha IIb beta 3 integrin-mediated tumor-cell spreading on fibronectin.

Tumor-cell interaction with the vessel wall during metastasis involves adhesion, induction of endothelial-cell retraction and spreading on the exposed sub-endothelial matrix. The signals for initiation of tumor-cell spreading and the receptors involved are unknown. A protocol was developed to distinguish between initial tumor-cell (B16 amelanotic melanoma; B16a) adhesion to and spreading on fibronectin. The time for maximum spreading was 50 min. Treatment with a lipoxygenase metabolite of arachidonic acid [12(S)-HETE] resulted in maximum spreading in 15 min (max. effect approx. 0.1 microM). Other lipoxygenase metabolites were ineffective. 12(S)-HETE treatment induced a rearrangement of F-actin, vinculin, vimentin intermediate filaments and integrin alpha IIb beta 3, but not integrin alpha 5 beta 1. Antibodies to alpha IIb beta 3 but not alpha 5 beta 1 blocked the 12(S)-HETE effect on B16a spreading. B16a-cell attachment to fibronectin resulted in increased metabolism of arachidonic acid to 12(S)-HETE, which was inhibited by lipoxygenase but not by cyclo-oxygenase inhibitors. Accordingly, lipoxygenase inhibitors but not cyclo-oxygenase inhibitors blocked spontaneous B16a-cell spreading. The protein-kinase-C inhibitors calphostin C, H7 and staurosporine also inhibited spreading, while the protein-kinase-A inhibitor H8 was ineffective. These data suggest that B16a-cell spreading on fibronectin is initiated by a lipoxygenase metabolite [12(S)-HETE] of arachidonic acid and is mediated by protein kinase C.     

Novel anti-tumour activity of 2,3,5-trimethyl-6-(3-pyridylmethyl)-1,4- benzoquinone (CV-6504) against established murine adenocarcinomas (MAC).

2,3,5-Trimethyl-6-(3-pyridylmethyl)1,4-benzoquinone (CV-6504), an inhibitor of 5-lipoxygenase and thromboxane A2 synthase and a scavenger of active oxygen species, has been shown to exhibit profound anti-tumour activity against three established murine adenocarcinomas (MACs) that are generally refractory to standard cytotoxic agents. For the cachexia-inducing MAC16 tumour, optimal anti-tumour activity was seen at dose levels of 10 and 25 mg kg-1 day-1, together with a reversal of cachexia and a doubling of the time to sacrifice of the animals through cachexia from 8 days to 17 days. The remaining tumour fragments showed extensive necrosis in regions distal from the blood supply. Growth of the MAC13 tumour was also effectively suppressed at dose levels between 5 and 50 mg kg-1 day-1, resulting in a specific growth delay between 1.0 and 1.2. Growth of the MAC26 tumour was also inhibited a concentration-related manner, with doses of 25-50 mg kg-1 day-1 being optimal. Anti-tumour activity towards all three tumours at low dose levels of CV-6504 was effectively suppressed by concurrent administration of linoleic acid (1 g kg-1 day-1), suggesting that inhibition of linoleate metabolism was responsible for the anti-tumour effect. Tumour sensitivity may be correlated with increased DT-diaphorase that are required to metabolise CV-6504 to the active hydroquinone, which inhibits 5-lipoxygenase activity.     

Biosynthesis of prostaglandins and hydroxy fatty acids in primary squamous carcinomas of head and neck in humans

The metabolism of [14C]arachidonic acid into cyclooxygenase and lipoxygenase products by homogenates of primary squamous carcinomas of head and neck in 12 patients was studied in vitro. The lipoxygenase pathway was predominant in all samples. The major metabolites were 12-hydroxy-5,8,11-14-eicosatetraenoic acid, (12-HETE) and 15-HETE. 5-HETE, 5,12-diHETE, 8-HETE and 9-HETE were also detected. The cyclooxygenase products detected were in the following order: PGE2 greater than PGF2 alpha greater than TxB2 greater than 15-keto-PGE2 greater than 6-keto-PGF1 alpha greater than PGD2. Literature review of the biological activities of these oxygenated metabolites of arachidonic acid suggest important modulatory roles in the pathophysiology of head and neck cancer.     

血小板型12-脂加氧酶与肿瘤

花生四烯酸通过脂加氧酶(lipoxygenase,LOX)途径代谢产生多种生物活性脂类,这些脂类在炎症、血栓形成和肿瘤演进过程中发挥着重要的作用。LOX按照组织分布被分为5- 、8- 、12 -、15- LOX4 个家族,血小板型12 LOX是LOX的一种,催化花生四烯酸转化为廿碳四烯酸。血小板型12 -LOX在正常组织中主要分布在血小板、人皮肤表皮细胞细胞质和微粒体中。近来研究发现,在多种肿瘤组织和肿瘤细胞系中不仅可检测到血小板型12- LOX的表达,且随着肿瘤级别的增高,瘤细胞表达增强。血小板型12 -LOX催化的代谢产物,如12(S) 羟廿碳四烯酸,已被证明涉及肿瘤细胞凋亡、肿瘤血管形成,因此血小板型12 LOX也成为肿瘤治疗的潜在目标。多项研究表明,血小板型12 -LOX的抑制剂能有效抑制肿瘤,如去甲二氢愈创木酸能有效抑制胶质瘤。对血小板型12- LOX与肿瘤细胞增殖、凋亡和血管生成之间的关系以及其机制进行讨论,另外,对血小板型12- LOX抑制剂预防和治疗肿瘤予以综述。     

Bidirectional control of membrane expression and/or activation of the tumor cell IRGpIIb/IIIa receptor and tumor cell adhesion by lipoxygenase products of arachidonic acid and linoleic acid

Lewis lung carcinoma cells express a plasma membrane receptor (i.e., IRGpIIb/IIIa) which is immunologically and functionally related to the platelet aggregation receptor complex (i.e., GpIIb/IIIa). Both fluorescence microscopy and flow cytometric analysis reveal that surface expression and/or activation of this tumor cell receptor is enhanced by a phorbol ester [i.e., 12-O-tetradecanoylphorbol-13-acetate (TPA)] and a lipoxygenase metabolite of arachidonic acid; 12-hydroxyeicosatetraenoic acid (i.e., 12-HETE). TPA-enhanced expression appears to be mediated by a lipoxygenase metabolite, as this effect can be reversed by lipoxygenase inhibitors but not by cyclooxygenase inhibitors. In parallel with these results both TPA and 12(S)-HETE [but not 12(R)-HETE] enhance tumor cell adhesion to endothelial cells, subendothelial matrix and fibronectin, but not to type IV collagen. TPA-enhanced adhesion can be reduced by lipoxygenase inhibitors but not by cyclooxygenase inhibitors and in addition, stimulated adhesion can be blocked by pretreatment of tumor cells with specific polyclonal or monoclonal antibodies which react against IRGpIIb/IIIa. 12(S)-HETE-enhanced adhesion can also be inhibited by these same antibodies. In contrast, a lipoxygenase product of linoleic acid, 13(S)-hydroxyoctadecadienoic acid, inhibited TPA and 12(S)-HETE-enhanced tumor cell adhesion to endothelial cells, subendothelial matrix, and fibronectin. These results suggest that (a) IRGpIIb/IIIa is a multifunctional receptor which mediates tumor cell adhesion to a variety of biological substrata, (b) TPA enhances surface expression and/or activation of this receptor possibly via a lipoxygenase metabolite of arachidonic acid, and (c) these effects are opposed by a lipoxygenase metabolite of linoleic acid.     

12-Lipoxygenases and 12(S)-HETE: role in cancer metastasis

Arachidonic acid metabolites have been implicated in multiple steps of carcinogenesis. Their role in tumor cell metastasis, the ultimate challenge for the treatment of cancer patients, are however not well-documented. Arachidonic acid is primarily metabolized through three pathways, i.e., cyclooxygenase, lipoxygenase, and P450-dependent monooxygenase. In this review we focus our attention on one specific lipoxygenase, i.e., 12-lipoxygenase, and its potential role in modulating the metastatic process. In mammalian cells there exist three types of 12-lipoxygenases which differ in tissue distribution, preferential substrates, and profile of their metabolites. Most of these 12-lipoxygenases have been cloned and sequenced, and the molecular and biochemical determinants responsible for catalysis of specific substrates characterized. Solid tumor cells express 12-lipoxygenase mRNA, possess 12-lipoxygenase protein, and biosynthesize 12(S)-HETE [12(S)-hydroxyeicosatetraenoic acid], as revealed by numerous experimental approaches. The ability of tumor cells to generate 12(S)-HETE is positively correlated to their metastatic potential. A large collection of experimental data suggest that 12(S)-HETE is a crucial intracellular signaling molecule that activates protein kinase C and mediates the biological functions of many growth factors and cytokines such as bFGF, PDGF, EGF, and AMF. 12(S)-HETE plays a pivotal role in multiple steps of the metastatic cascade encompassing tumor cell-vasculature interactions, tumor cell motility, proteolysis, invasion, and angiogenesis. The fact that 12-lipoxygenase is expressed in a wide diversity of tumor cell lines and 12(S)-HETE is a key modulatory molecule in metastasis provides the rationale for targeting these molecules in anti-cancer and anti-metastasis therapeutic protocols.     

In Vitro Proliferation of Fibrosarcoma Cells Depends on Intact Functions of Lipoxygenases and Cytochrome P-450-Monooxygenase

Proliferation of mouse fibrosarcoma cells G:5:113 was studied in vitro after affecting particular pathways of arachidonic acid metabolism by selected inhibitors. After 48 hours of cultivation with nonspecific lipoxygenase inhibitors, nordihydroguaiaretic acid (NDGA) and esculetin; a specific 12-lipoxygenase inhibitor, baicalein; and inhibitor of five-lipoxygenase activating protein, MK-886, markedly suppressed the number of cells and induced significant changes in cell cycle distribution in a dose-dependent manner. While proadifen, an inhibitor of cytochrome P-450-monooxygenase, applied in low concentrations, increased the cell number, at higher concentrations, it inhibited cell proliferation and significantly changed the cell cycle. Cyclooxygenase inhibitors, ibuprofen, flurbiprofen, and diclofenac suppressed cell numbers only moderately without any changes in the cell cycle. The occurrence of apoptosis was not significant for any of the selected drugs in comparison with untreated control cells. Moreover, not even one of the drugs caused the specific cleavage of poly (ADP-ribose) polymerase to the 89-kDa fragment, however, a decrease in total amount of this protein was observed after treatment with NDGA and esculetin. We conclude that the proliferation ability of fibrosarcoma cells G:5:113 in vitro depends on intact functions of 5-lipoxygenase, 12-lipoxygenase, and cytochrome P-450-monooxygenases, and that the effects of inhibitors do not include regulation of apoptosis.     

In vitro proliferation of fibrosarcoma cells depends on intact functions of lipoxygenases and cytochrome P-450-monooxygenase

Proliferation of mouse fibrosarcoma cells G:5:113 was studied in vitro after affecting particular pathways of arachidonic acid metabolism by selected inhibitors. After 48 hours of cultivation with nonspecific lipoxygenase inhibitors, nordihydroguaiaretic acid (NDGA) and esculetin; a specific 12-lipoxygenase inhibitor, baicalein; and inhibitor of five-lipoxygenase activating protein, MK-886, markedly suppressed the number of cells and induced significant changes in cell cycle distribution in a dose-dependent manner. While proadifen, an inhibitor of cytochrome P-450-monooxygenase, applied in low concentrations, increased the cell number, at higher concentrations, it inhibited cell proliferation and significantly changed the cell cycle. Cyclooxygenase inhibitors, ibuprofen, flurbiprofen, and diclofenac suppressed cell numbers only moderately without any changes in the cell cycle. The occurrence of apoptosis was not significant for any of the selected drugs in comparison with untreated control cells. Moreover, not even one of the drugs caused the specific cleavage of poly (ADP-ribose) polymerase to the 89-kDa fragment, however, a decrease in total amount of this protein was observed after treatment with NDGA and esculetin. We conclude that the proliferation ability of fibrosarcoma cells G:5:113 in vitro depends on intact functions of 5-lipoxygenase, 12-lipoxygenase, and cytochrome P-450-monooxygenases, and that the effects of inhibitors do not include regulation of apoptosis.     

Role of eicosanoids in prostate cancer progression

Metabolism of arachidonic acid through cyclooxygenase, lipoxygenase, or P450 epoxygenase pathways leads to the formation of various bioactive eicosanoids. In this review, we discuss alterations in expression pattern of eicosanoid-generating enzymes found during prostate tumor progression and expound upon their involvement in tumor cell proliferation, apoptosis, motility, and tumor angiogenesis. The expression of cyclooxygenase-2, 12-lipoxygenase, and 15-lipoxygenase-l are up-regulated during prostate cancer progression. It has been demonstrated that inhibitors of cyclooxygenase-2, 5-lipoxygenase and 12-lipoxygenase cause tumor cell apoptosis, reduce tumor cell motility and invasiveness, or decrease tumor angiogenesis and growth. The eicosanoid product of 12-lipoxygenase, 12(S)-hydroeicosatetraenoic acid, is found to activate Erkl/2 kinases in LNCaP cells and PKC in rat prostate AT2.1 tumor cells. Overexpression of 12-lipoxygenase and 15-lipoxygenase-l in prostate cancer cells stimulate prostate tumor angiogenesis and growth, suggesting a facilitative role for 12-lipoxygenase and 15-lipoxygenase-l in prostate tumor progression. The expression of 15-lipoxygenase-2 is found frequently to be lost during the initiation and progression of prostate tumors. 15(S)-hydroxyeicosatetraenoic acid, the product of 15-lipoxygenase-2, inhibits proliferation and causes apoptosis in human prostate cancer cells, suggesting an inhibitory role for 15-lipoxygenase-2 in prostate tumor progression. The regulation of prostate cancer progression by eicosanoids, in either positive or negative ways, provides an exciting possibility for management of this disease.     

Constitutive expression of 8-lipoxygenase in papillomas and clastogenic effects of lipoxygenase-derived arachidonic acid metabolites in keratinocytes

The expression pattern, enzymatic activity, and products of 8-lipoxygenase (LOX) were analyzed in normal and neoplastic skin of NMRI mice. While barely detectable in normal epidermis, 8-LOX was transiently induced by 12-O-tetradecanoylphorbol-13-acetate and constitutively expressed in papillomas but not carcinomas obtained by the initiation-promotion protocol of mouse skin carcinogenesis. The product profile and chirality of both the native and the recombinant protein produced the S enantiomers of 8-hydroxy-5Z,9E,11Z,14Z-eicosatetraenoic acid (8-HETE) and 9-hydroxy-10E,12Z-octadecadienoic acid (9-HODE) as the main arachidonic acid- and linoleic acid-derived metabolites. As compared with normal epidermis, papillomas exhibited 25- and 4-fold elevated levels of 8-HETE and 9-HODE, respectively. However, the varying S to R ratios of 8-HETE and the predominance of 9(R)-HODE indicated that in addition to 8(S)-LOX, other enzymes yet to be defined may be involved in 8-HETE and 9-HODE production. The massive accumulation of both 8-HETE and 12-hydroxy-5Z,8Z,10E,14Z-eicosatetraenoic acid (12-HETE) point to a critical role of these LOX pathways in epidermal tumor development, in particular in the papilloma stage. Here we showed that 8- and 12-hydroperoxyeicosatetraenoic acids and 8- and 12-HETE induce chromosomal alterations in cycling primary basal keratinocytes.     

Lipoxygenase inhibitors for the treatment of pancreatic cancer

Pancreatic cancer has a dismal prognosis with no effective medical therapy. Therefore, there is a need to search for novel targets for cancer prevention and treatment. The lipoxygenases oxygenate arachidonic acid and other 20-carbon fatty acids and their downstream metabolites have been found to mediate several aspects of pancreatic cancer development and growth. Therapeutic agents have been developed against various targets in the lipoxygenase pathways. Many of these were first developed for their anti-inflammatory properties and were subsequently found to have anticancer effects. Such agents include lipoxygenase and 5-lipoxygenase-activating protein inhibitors, leukotriene receptor antagonists and natural products with inhibitory effects on these pathways. Dual lipoxygenase and cyclooxygenase inhibition represents an exciting area of research and drug development.     

Lipoxygenase inhibitors for the treatment of pancreatic cancer

Pancreatic cancer has a dismal prognosis with no effective medical therapy. Therefore, there is a need to search for novel targets for cancer prevention and treatment. The lipoxygenases oxygenate arachidonic acid and other 20-carbon fatty acids and their downstream metabolites have been found to mediate several aspects of pancreatic cancer development and growth. Therapeutic agents have been developed against various targets in the lipoxygenase pathways. Many of these were first developed for their anti-inflammatory properties and were subsequently found to have anticancer effects. Such agents include lipoxygenase and 5-lipoxygenase-activating protein inhibitors, leukotriene receptor antagonists and natural products with inhibitory effects on these pathways. Dual lipoxygenase and cyclooxygenase inhibition represents an exciting area of research and drug development.     

Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib.

PURPOSE: Previous studies have suggested an important role of aberrant arachidonic acid metabolism, especially the cyclooxygenase (Cox) pathway, in oral carcinogenesis. However, it is unknown whether the 5-lipoxygenase (5-Lox) pathway contributes to oral carcinogenesis, and whether combination of inhibitors of both pathways may have synergistic or additive effects of chemoprevention. EXPERIMENTAL DESIGN: 5-Lox expression was examined in 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster and human oral cancer tissues by immunohistochemistry, and Cox2 expression was investigated in hamster oral tissues using in situ hybridization. Zileuton (a specific 5-Lox inhibitor) and celecoxib (a specific Cox2 inhibitor), either alone or in combination, were investigated for their chemopreventive effects on the DMBA-induced hamster model at the post-initiation stage through topical application. RESULTS: 5-Lox was overexpressed during oral carcinogenesis in hamsters and humans, as well as Cox2 in the hamster tissues. In a chemoprevention study using the post-initiation DMBA model, incidence of hamster oral squamous cell carcinoma was reduced from 76.9% (20 of 26) to 45.8% (11 of 24, P < 0.05) and 32.1% (9 of 28, P < 0.01) by 3% and 6% topical zileuton, respectively; and to 57.6% (15 of 26, P > 0.05) and 50% (12 of 24, P < 0.05) by 3% and 6% topical celecoxib, respectively. When used in combination, celecoxib and zileuton (3% of each) had an additive inhibitory effect on the incidence of squamous cell carcinoma (36%, 9 of 25, P < 0.01). Other pathologic variables and the levels of leukotriene B4 and prostaglandin E2 of the hamster tissues were reduced as well. CONCLUSIONS: The results clearly showed that both 5-Lox and Cox2 played important roles in oral carcinogenesis. Zileuton and celecoxib prevented oral carcinogenesis at the post-initiation stage through their inhibitory effects on arachidonic acid metabolism.     

Inhibitors of lipoxygenase have antiproliferative effects on P815 murine mastocytoma cells

The effect of a variety of inhibitors of prostaglandin synthase, lipoxygenase and phospholipase on the growth of P815 murine mastocytoma cells was examined. Only lipoxygenase inhibitors substantially reduced growth, presumably by inhibiting the production of arachidonic acid metabolites rather than causing arachidonate accumulation since excess arachidonic acid did not reverse growth inhibition. Evidence is presented that production of leukotrienes B4, C4, D4 or E4 was not involved. Other metabolites of arachidonic acid were not excluded. A role for lipoxygenase in growth signal transduction in these and other cells is suggested.