Cyclooxygenase and lipoxygenase inhibitors in cancer therapy

Review

Prostaglandins, Leukotrienes and EssentiaI Fatty Acids (f996) 54, 3-16

© PearsonProfessionalLtd 1996

C y c l o o x y g e n a s e and lipoxygenase inhibitors in c a n c e r therapy G. Ara and B. A. Teicher Division of Cancer Pharmacology, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA

INTRODUCTION

Tumor growth, vascularization, invasion, and metastasis require activation and/or proliferation of specific host cells, and, perhaps, deactivation and/or suppression of others. Growth in vivo requires that tumor cells restructure the surrounding extraceUular matrix, initiate proliferation of critical normal cells, and perhaps, alter host defence systems/-3 all of which may depend on intracellular signalling, autocrine and paracrine functions of various types of growth factors, and possibly angiogenesis. The networks of communication through intercellular signalling continue to be implicated in many of the checks and balances in various normal and malignant tissues. 4-7 Arachidonic acid (AA) is a fatty acid which is synthesized from dietary linoleic acid (LA). Metabolic products of the three AA pathways are known to be involved in several intercellular signalling processes and regulations of growth factors,4-z immune r e s p o n s e s y 4 macrophage induction 15-21 and angiogenesis. 22 The AA cascade generates a family of bioactive lipids that modulate diverse physiological and pathological responses including tumor growth and promotion. 4-7 Eicosanoids are metabolites of AA. In recent years there have been numerous publications describing the roles of AA metabolites in various types of tumors. The inhibition of cyclooxygenase and lipoxygenase activities by non-steroidal anti-inflammatory drugs and their effects on tumor growth and promotion have also been reported. In this review we have attempted to consolidate much of this work relating to mammary, lung, colon, and head and neck cancers. Based on these studies, we have also tried to reach a consensus of this literature from which to propose future research directions. Correspondence to: Gulshan Ara, Tel. (617) 735 8942

F U N C T I O N S OF A R A C H I D O N I C ACID METABOLITES

Arachidonic acid (AA) is an essential fatty acid consumed in the diet or derived from elongation and desaturation of dietary linoleic acid (LA).4AA metabolism is linked to signal transduction pathways that result in the activation of phospholipase C (PLC) and phospholipase A2 (PLA2).23-26 Once AA is released from phospholipids it is oxidized by one of three different oxygenases (Fig. 1). 4'27 A certain cytochrome P-450 inserts a single oxygen atom into the double bond of AA to produce epoxy-arachidonic acids. 2r Lipoxygenases introduce one molecule of 02 into the carbon framework of AA to produce a series of isomeric hydroperoxy acids. 2s These hydroperoxy fatty acids are converted to hydroxy fatty acids, to leukotrienes (LTs)and t o l i p o x i n s . 4,27,28 Cyclooxygenase introduces two molecules of 02 into AA to form the hydroperoxy endoperoxide prostaglandin (PG) G2, which is reduced by the peroxidase activity to the hydroxy endoperoxide, PGH2 .4,29-31PGH2 is transformed to PGs, thromboxanes (TXs), prostacyclin, and malondialdehyde? The physiological response to AA oxygenation in a given tissue is largely determined by the levels of PGH2-metabolizing enzymes in the cells making up that tissue. Each PG has its own range of biological activities. The LTs constitute a family of highly potent inflammatory mediators which are derived from the 5lipoxygenase pathway of AA metabolism. 32-34 Eicosanoids are not stored but are synthesized on demand; therefore inhibitors of the various oxygenases and peroxidemetabolizing enzymes have instantaneous effects on eicosanoid levels? 5,36 Unraveling the role of PGs and LTs in tumor promotion is a perplexing task. Although there has been great deal of interest in the involvement of A_A metabolites in cancer, there is uncertainty about which metabolites are the most

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Ara and Teicher

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Fig. 1 Cyclooxygenase and lipoxygenase pathways of AA metabolism. Metabolites of cyclooxygenase pathway are called prostaglandins G2 (PGGa), E2 (PGE2), H2 (PGH2), D2 (PGD2), F2~ (PGFa~), thromboxane A2 (TXA2), malondialdehyde (MDA), and prostacyclin (PGla). Metabolites of the lipoxygenase pathway are called 12- and 5-hydroperoxyeicosatetraenoicacids (HPETEs), and their corresponding fatty acids (HETEs). Leukotriene A synthase (LTA synthase) generates the leukotrienes.

important and how they contribute to specific steps in cell transformation, tumor growth, and metastasis. Since their discovery in the 1930s, PGs have been found to play a role in a wide variety of physiologic processes. Aberrations in PG metabolism have also been implicated in pathologic states? z The role of various PGs in vascular and renal physiology and pathology has been well characterized? However, the role of PGs in malignant disease is less clear. PG synthesis inhibitors have been found to decrease tumor growth in experimental systems. Also, human malignancies, especially breast and lung cancer, have been found to synthesize large amounts of PGs2Z-~8 Increased levels of PGE in body fluids and in tumor tissues were found in patients with various malignant tumors? 9-61 However, the biological significance of these findings have not yet been clearly established. Thus, in some studies the production of PGE was found to correlate with malignancy and aggressiveness, whereas in others this correlation was not found. In some tumor systems, the content or production of PGE was not increased Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 54, 3-16

in comparison to normal tissue, or its level in blood was not increased 6z or PGE was not even detectable in the blood. 63 Cyclooxygenase and lipoxygenase inhibitors

A trademark for PGH synthase is inhibition of its cyclooxygenase activity by a variety of agents known collectively as non-steroidal anti-inflammatory drugs. 63-zl The best known of these are the cyclooxygenase inhibitors aspirin, indomethacin, ibuprofen, piroxicam, and sulindac (Fig. 2). Aspirin is a competitive inhibitor and also covalenfly modifies the PGH synthase protein, whereas indomethacin, ibuprofen, piroxicam, and sulindac are competitive inhibitors that do not bind covalently to the protein. 67-zl Indomethacin has been demonstrated to form a tight 1:1 complex with PGH synthase and dissociate very slowly?6 A small, relatively hydrophilic compound of the Nhydroxyurea class, A-69412, is a promising compound which is a long acting 5-1ipoxygenase inhibitor, zz,z3Other © Pearson Professional Ltd 1996

Cyclooxygenase and lipoxygenase inhibitors in cancer therapy 5

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Fig, 2 Structures of some common non-steroidal anti-inflammatory drugs which act by inhibitingthe cyclooxygenase pathway,

lipoxygenase inhibitors are phenidone, 68-7° zileuton,7a-75 curcumin,76 esculin, 77 and nordihydroguaiaretic acid45,46 (Fig. 3). Effects of PG and LT inhibition on tumor growth

Although there have been numerous reports on the role of AA metabolites on various types of tumors, the majority of the work has concentrated on mammary, lung, colon, and head and neck cancer. In this review we have attempted to summarize most of the work done concerning these tumors. Mammary tumors

At present, there is considerable interest in the role of eicosanoids in breast cancer. Studies of human mammary tumors have demonstrated that levels of several eico-

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Fig, 3 Structures of some common non-steroidal anti-inflammatory drugs which act by inhibitingthe lipoxygenase pathway.

© Pearson Professional Ltd 1996

sanoids are increased in breast cancer in comparison to benign breast tumors.44,78High PG synthetic activity was reported to be associated with histologically aggressive human breast tumors. Numerous studies investigated the modulation of eicosanoid synthesis through the inhibition of various pathways of AA metabolism,w,45-sS,72-79 The majority of preclinical studies in this area have explored the use of inhibitors of the cyclooxygenase pathway to inhibit tumor growth. The growth of most transplantable rodent mammary tumors is inhibited by treatment with indomethacin. Fulton reported that whereas the growth of 410 and 4526 mouse mammary tumors was inhibited by indomethacin in vivo, indomethacin stimulated proliferation of the 410 and 4526 mouse mammary tumor cells in vitro. 49 Lee et al and McCormick et al showed that a lipoxygenase inhibitor, nordihydroguaiaretic acid, and esculletin can inhibit rat mammary TMT-081 tumor cell growth and rat mammary carcinogenesis induced by N-methyl-N-nitrosourea (MNU).39,46,47,79The TMT-081 rat mammary tumor cell line was shown to metabolize exogenous AA to a variety of oxygenated metabolites, e.g. the cyclooxygenase products, TXB2, PGE2, and PGF2~ and at least one lipoxygenase product, 12- and/or 15-hydroxyeicosatetraenoic acid (12- and/or 15-HETE). This demonstrates that this cell line contains both cyclooxygenase and lipoxygenase activities. Lee et als9 have shown that inhibitors of cyclooxygenase and/or lipoxygenase inhibited cell growth in a concentration-dependent manner. It has been also reported that both ibuprofen and indomethacin which inhibit cyclooxygenase activity stimulated the synthesis of 12- and/or 15-HETE in TMT-081 cells. This might indicate that inhibition of cyclooxygenase activity shunts more AA for m~ ~abolism through the lipoxygenase pathway. Lee et ala9 also reported that the lipoxygenase inhibitor, esculetin, stimulated the formation of all cyclooxygenase metabolites without significantly affecting the lipoxygenase pathway. Also, BW755C and timegadine, akhough known as inhibitors of cyclooxygenase and lipoxygenase,8°-82 were more effective in inhibiting the cyclooxygenase pathway than the lipoxygenase pathway. Lee et al (39) also reported that TXB2,PGE2, PGF2~,and 12and 15-HETE stimulate DNA synthesis in TMT-081 cells. Experiments with piroxicam, nordihydroguaiaretic acid, and esculetin, other inhibitors of eicosanoid biosynthesis with varying selectivity for enzymes of the PG and LT pathways, indicated that MDA-MB-231 cell growth was dependent on LT rather than PG production.8°,82Corey et alsa found decosahexaenoic acid to be an inhibitor of PG synthesis and to a lesser extent of the lipoxygenase responsible for LT biosynthesis from AA. They also reported that in a dietary study of mammary carcinogenesis induced by dimethylbenz(a)anthracene, feeding n-3 fatty acid-rich menhaden oil not only lowered tumor incidence Prostaglandins, Leukotrienes and Essential FattyAcids (1996) 54, 3-16

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but caused a reduction in both LTB4 and PGE levels in the tumors which did develop. Indomethacin inhibited MDA-MB-231 cell growth and suppressed the otherwise stimulatory effect of LA. Studies have also attempted to correlate the effects of cyclooxygenase inhibition on PG production and mammary t u m o r g r o w t h . 39,50,83-88 However, no direct correlation between changes in a specific product and drug effect have been derived. Bandyopadhyay et al,89 using mouse mammary epithelial cells grown within collagen gels, demonstrated that PGs stimulate growth only in the presence of epidermal growth factor (EGF) (10 ng/ml). In a later study9° they found a suboptimal dose of EGF (1 ng/ ml) which showed a better response for growth inhibition. Colon tumors

Large bowel cancer is one of the leading causes of cancer deaths in Western countries including North AmericaY ~ PC inhibitors such as piroxicam, indomethacin, sulindac, and aspirin, inhibit colon tumorigenesis in rodents? ,92 Lipoxygenase metabolites such as (12S)-HETE promote tumor cell adhesion, stimulate tumor cell spreading and augment the tumor cell metastatic potential. 9a-9~A positive correlation was observed between the levels of (85)HETE and the degree of inflammation, hyperproliferation, and tumor development induced by 12-O-tetradecanoylphorbol-13-acetate?6 In addition, the activities of (55)and (15S)-HETE, which are potent modulators of inflammation suppressed by lipoxygenase inhibitors, indicate a mediating role of HETEs in colon tumor promotion?Zgs Curcumin, which possesses both anti-inflammatory and antioxidant properties, caused a reduction in the formation of PGs such as PGE2, PGF2~,PGD2, 6-keto-PGF~ and TXB 2 through the cyclooxygenase system and production of (5S)-, (8S)-, (125)-, and (15S)-HETE via the lipoxygenase pathway from AA in rats and reduced the growth of colon carcinoma.76 In rat models of colon carcinogenesis, cyclooxygenase inhibitors such as indomethacin, piroxicam, and sulindac exhibit chemopreventive effects as judged by reductions in the number of tumor-bearing animals and the numbers of tumors per animal.76 In the case of piroxicam, a dose response was observed, and there was approximately a 70% reduction in tumor incidence. Waddell et al99 first reported that sulindac reduced the size and number of rectal polyps in individuals with familial polyposis who had undergone subtotal colectomy and ileoproctostomy. Subsequently, they reported that sulindac induced regression of tumors in affected individuals who had no previous surgical treatment. When sulindac administration was discontinued, the tumors recurred and resumption of sulindac treatment caused tumor regression. The reduced form of sulindac is a cyclooxygenase inhibitor, and its ability to induce polyp Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 54, 3-16

regression may support the hypothesis that cyclooxygenase inhibition is important to reduce colon cancer. Narisawa et al~oo demonstrated that venous blood draining from colon tumors contains large amounts of PGE2 and that the larger the tumor, the higher is the PGE2 output. The levels of PGE2 synthesized by the tumors and present in venous blood correlate with the extent of invasion of surrounding tissue. Other laboratories have reported that colon tumors produce high levels of PGs, most commonly PGE2 .4'z1°1'1°2 Recently, Rao et a176reported on the chemoprevention of colon carcinogenesis by sulindac. They showed that the administration of 160 and 320 ppm sulindac before, during, and after carcinogen treatment significantly suppressed colon adenocarcinoma formation in a dosedependent manner. Previously, they had also shown that the administration of sulindac inhibited 1,2-dimethylhydrazine- and azoxymethane-induced intestinal tumor formation in mice and rats, respectively?°2 Lung tumors The PGs and related eicosanoids are important mediators of normal lung function1°3-1°sand might also be important in the pathophysiology of human lung cancers s,1°5-"° Since lung is a tissue rich in enzymes that biosynthesize PGs and TXs, the biosynthetic capability of lung tumor tissue to synthesize this family of compounds might be useful in the classification of lung cancer and provide a better understanding of the role of PGs and TXs in the pathophysiology of this disease? °s-lls It has been suggested that there may be characteristic perturbations in PG biosynthesis in certain human lung cancers in vivo TM and in lung cancer tissue in vitro, l°z Since PGs may be important as mediators of normal pulmonary function as well as in the modulation of certain components of the immune responsey 7,1'9-121 tumor promotion, Ha-H6,~21-~23 cellular proliferation, and tumor cell metastasis, comparison of PG biosynthetic profiles in normal lung and lung cancer tissues may provide additional insight into the role of this family of compounds in the pathophysiology of human lung cancer. McLemore et al~23have suggested that elevated PGE2 levels might provide a selective advantage for tumor cell survival in the microenvironment of the lung. Individual comparison of PG biosynthesis according to lung cancer histological cell type revealed that PGE2 and PGF2~ were consistently elevated in four primary lung cancer histological cell types. 123 Non-small-cell lung cancer is traditionally regarded as a chemotherapy-refractory disease. TM The lung cancer cell lines that secrete the PGs are bronchioalveolar cell adenocarcinoma. It has been recognized for some time that the murine Lewis lung carcinoma secretes PGE2 and that administration of the PG synthesis inhibitor © Pearson Professional Ltd 1996

Cyclooxygenase and lipoxygenase inhibitors in cancer therapy 7

indomethacin begining at the time of tumor cell implantation can slow the growth and metastasis of the tumor? 4,125-~2zVarious non-small-cell lung carcinoma cell lines were reported to secrete PGE2 and PGF2~ into the cell culture medium at relatively high levels? 1-53 Tumor cell production of PGs has been associated with cell growth, mutagenesis and promotion, immune suppression, and metastasis? a,51-53 The effects of cyclooxygenase inhibitors on the growth of the Lewis lung carcinoma in C57/BL mice have been investigated in some detail. The Lewis lung carcinoma is a spontaneously arising lung tumor that has been used extensively for screening chemotherapeutic and antimetastatic agents. Lewis lung carcinoma tumor tissue synthesizes large amounts of eicosanoids and the major product is PGE2 .14 Aspirin and indomethacin significantly inhibit the growth of subcutaneous Lewis lung carcinoma but do not inhibit proliferation of Lewis lung carcinoma cells in culture at concentrations that inhibit PGE2 synthesis. The ability of indomethacin to inhibit the growth of the Lewis lung carcinoma in vivo correlates to its ability to prevent PGE2-dependent immunosuppression. 14,5°,51,126Indomethacin inhibits the growth of subcutaneous Lewis lung carcinoma if it is administered several days after the inoculation of tumor cells. However, if further tumor growth occurs before indomethacin administration, it is not an effective inhibitor. Thus, cyclooxygenase inhibitors do not appear to be good candidates for treatment of humans with large tumor burdens, s° Nevertheless, they may slow or prevent the growth of developing tumors. Hubbard et al50,51,126surveyed 54 different human tumor cell lines for PG biosynthetic capacity and found dramatic differences between cell lines of specific anatomical locations. They reported that the highest levels of PGs were produced by cell lines from non-small-cell lung cancer. Teicher et a1127 have used cyclooxygenase inhibitors (mefenamic acid, diflunisal, sulindac, and indomethacin) and the lipoxygenase inhibitor phenidone as modulators of cytotoxic therapies in Lewis lung cancer. Although varying degrees of modulation were reported for dsdiamminedichloroplatinum(II), cyclophosphamide, and BCNU treatment, no clear relationship between effective modulation of the cancer therapies and the degree of reduction in serum levels of PGE2 and LTB 4 w a s observed. Head and neck tumors

There is evidence which suggest that PGE2 plays an important role in the growth of head and neck carcinomas. The immunological reactivity in patients with these tumors was reported to be greatly depressed, and was correlated with increased PGE 2 production by the tumor. ~28,~29The decreased immunological reactivity can be substantially improved by the addition of indo© Pearson Professional Ltd 1996

methacin. Also, squamous head and neck carcinomas were found to contain 45 or produce 13° higher amounts of PGE2 compared with normal, unaffected oral mucosa. In some patients with head and neck carcinomas, elevated blood levels of PGs were observed in comparison to tumor-free patients? a°,~a~Klapan et al TM determined plasma PGE= levels in 53 patients with various stages (II, III, and IV) of hypolaryngeal and laryngeal squamous cell carcinoma. They have observed that PGE2 levels in cancer patients were proportional to the stage of the disease and higher than in non-cancer patients. The mean plasma PGE2 concentration significantly decreased for all tumor stages 15-30 d after surgical removal of the tumor. Other types of tumors

Numerous observations provide a circumstantial link between PG synthesis and the control of cell growth. PGF2~ stimulates mitogenesis in Swiss 3T3 fibroblasts at concentrations (2 ng/ml) 2-3 orders of magnitude lower than any other PGs. ~32TXA2 also stimulates cell growth. ~32 There is strong evidence for PG involvement in tumor promotion in epidermis of NMRI mice by phorbol esters.* Treatment of CD-1 and NMRI mice with the cyclooxygenase inhibitors indomethacin, aspirin, and flufenamic acid inhibits phorbol ester induction of orithine decarboxylase and mitogenesis.4,135-13s Inhibition can be overcome by co-administration of PGE~, or PGE2. Metastasis

The adhesion and migration characteristics of metastatic tumor cells are different from those of non-metastatic tumor cells and may be critical to the capacity of the cells to metastasize. 12°,135-142Tumor cells secrete many soluble factors, such as PGE2, which may alter tumor migration in vitro or metastasis in vivo. Numerous studies imply a role for eicosanoids in metastasis but there is no consensus on which eicosanoid is responsible or the mechanism(s) by which it acts. 143,144 Indeed, considerable variation is observed in the results of experiments conducted in different model systems. For example, treatment of B16 melanoma cells with indomethacin prior to injection into mice increased the number of metastatic lung colonies in an artificial metastasis model/45-~47 In contrast, treatment of a routine mammary adenocarcinoma with indomethacin prior to injection decreased the number of lung colonies? 51Infusion of pharmacological doses of PGE1 (intravenously) inhibits metastasis of Lewis lung carcinoma cells from a subcutaneous site (spontaneous metastasis) but enhances metastasis of Lewis lung carcinoma tumor cells tail vein-injected into mice (artificial metastasis). 39,a2 These conflicting results may reflect differences in the events necessary for lung colonization in different models and their sensitivity to tumor burden. The levels of two PGs (PGE and PGF) have been deterProstaglandins, Leukotrienes and Essential Fatty Acids (1996) 54, 3-16

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mined in a series of murine mammary lesions ranging from preneoplastic, hyperplastic alveolar nodules to highly metastatic adenocarcinomas.82 A highly positive correlation was seen between high levels of PGE and high tumorigenicity and metastatic potential. In addition, spontaneous metastasis of two highly metastatic tumors was partially inhibited by oral administration of indomethacin from the time of subcutaneous tumor transplantation until removal of the primary tumor. Cells of metastatic tumor lines were more resistant to killing than were cells of two non-metastatic tumor lines. Recently, it has been shown that 5-HETE, a 5-1ipoxygenase product, may be involved in tumor cell Invasion of basement membranes, the principal barrier for the dissemination of malignant cells to distant sites) 42 Elevated PG production was associated with increased metastasis formation by some t u m o r s . 122'12s'141-147 However, other studies have shown a negative correlation between PGE2 production and tumor metastasis capacity. 123,134-136 Effects of LA on the growth and metastasis of human breast cancer cell lines (estrogen receptor negative MDAMB-435 and MDA-MB-231) in nude mice and the invasive capacity of these cells in vitro has been examined by Rose et al.8~ The MDA-MB-231 cell lines exhibited a relatively high capacity for invasion in vitro and constitutively high levels of both total type IV collagenolytic activity and MW 92 000 gelatinase production which were unaffected by LA. In contrast, MDA-MB-435 cells had approximately only one-sixth the invasive capacity and secreted a relatively low level of type IV collagenase and little of the MW 92 000 gelatinase; both invasion and enzyme production were stimulated by LA.81 Young et aP4 showed that the plasma PGE2 concentrations, which ranged from 0.4 to 0.7 ng/ml for I_N7 tumorbearing mice implanted with control osmotic pumps, became elevated to a range of 2.7-3.9 ng/ml at 1 week after implantation of osmotic pumps releasing PGE2 and caused an increased number of lung tumor nodules. They also examined the in vitro effect of PGE2 on [3H]thymidme incorporation by Lewis lung cells and showed that neither the inhibition of PG synthesis with indomethacin nor the addition of PGE2 altered the incorporation of [3H]thymidine by the metastic tumor cells. A N T I T U M O R ACTIVI'rY OF PROSTAGLANDINS

Although many reports have described the effects of PGs on tumor promotion and metastasis, there is also literature describing the antitumor activity of synthetic PG analogs. Since the 1970s it has been well known that PGs of the E and A series inhibit the growth of many lines of tumor cells in vitro and in vivo?z PGJ2 and related compounds continue to be of interest in areas including Prostaglandins, Leukotrienes and Essential Fatty Acids (1996) 54, 3-16

pharmacology, oncology, molecular biology, and immunology and a comprehensive review of this topic was published in 1992. TM Since alkylidene cyclopentenone eicosanoids show potent antitumor activity, 148,'49chemists have developed newer, easier methods for the synthesis of this class of eicosanoids. Liebeskind et al described highly stereoselective, palladium-catalyzed reactions that yielded a 4-0xygenated 5-alkylidine cyclopentenone derivative synthesized by this new method which displayed significant antitumor activity in vitroJ 48,149 Fukushima et aP ~° reported antitumor effects of PGD~ on the L1210 murine leukemia and human leukemia cell lines. Initially PGD2 was thought to be a very potent antitumor agent? 5~-154In vivo studies have demonstrated that there may be different tumor cell sensitivities to PGA, PGD, and PGJ series. Effects of antineoplastic PGs on human ovarian cancer cell growth were examined by using HR cells derived from ascites of a patient with serous cystadenocarcinoma of the ovary. ]53 With regard to inhibition of cancer cell proliferation in vitro, the effects of D7-PGA] was most marked, followed by that of D12PGJ2, PGJ2, and PGD2. When antineoplastic PGs were administered to nude mice bearing HR cells, tumor growth in groups treated with PGJ2 and D~2-PGJ2 alone was significantly inhibited compared to that in untreated controls. Also, a significant prolongation of median survival was observed when the conventional treatment with cisplatin was combIned with PGD2 or D7-PGA], compared to the resuks in groups treated with PGD2 alone, Dz-PGA~ alone or cisplatin alone. Using Lewis lung carcinoma in male B6D2F1 mice, Ellis et al3z52 examined the role of PGE1 in tumor growth and metastasis. Mice underwent Intravenous catheterization and were infused with either PGE~ at 3 ~g/kg/min or 6 ~tg/ kg/min, indomethacin at 1 ~g/kg/min or normal saline. After 10 days of infusion, tumor volume, tumor weight, and the number of metastases greater than 2 mm in diameter were significantly decreased, and tumor doubling time was significantly prolonged in the group receiving 6 ~g/kg/min of PGE~ compared to those treated with saline, indomethacin, or a dose of 3 ~g/kg/min of PGE2. The authors have proposed that PGE~ may potentiaUy serve as a chemotherapeutic agent or a component of chemotherapeutic regimens. PGE~ has been found to be cytoprotective to the gastrointestinal tract and thus may serve to limit the severity of chemotherapeutically Induced gastrointestinal toxicity. Antitumor effect of cyclopentenone PGs on various kinds of tumors continue to be studied in vitro and In vivo. Conde et al156have studied the effects of PGD2 on C6 rat glioma cell differentiation and proliferation. CasteUi et al]57 determined AA metabolites in specimens of human intracranial tumors and reported that rapidly growing infiltrating gliomas had higher synthesis of TXA2, which © Pearson Professional Ltd 1996

Cyclooxygenase and lipoxygenase inhibitors in cancer therapy

has been reported to be a pro-cancer metabolite, whereas synthesis of PGD2 and PGI2 which have been reported to be anti-cancer eicosanoids, were diminished.

MECHANISMS Effects of AA metabolites on macrophage activation and immune response

One of the mechanisms by which cyclooxygenase inhibitors may reduce tumorigenesis has been proposed to be by modulation of the immune response. 8-1~ AA metabolites may play a modulatory role in several immunological and inflammatory diseases. The growth of various tumors is associated with immune suppression in humans and animals. Colony-stimulating factors released by tumor cells activate monocytes and macrophages to synthesize PGE2 which inhibits blastogenesis of T-cells and the cytotoxic activity of natural killer cells. Cyclooxygenase inhibitors such as aspirin, indomethacin, piroxicam, and flurbiprofen abolish PGE2 synthesis and attenuate the immune suppression. H,~57-~1This may contribute to their ability to reduce tumor growth in several animal models, including the colon. In in vitro studies, PGE2 has been found to decrease lymphokine production, whereas interleukin-1 and interleukin-2 increase PC production in monocytes. PGs act as important mediators of Inflammation by regulating the functions of the cell that participate in inflammatory and immune responses. Macrophages produce PGs and are also affected by them. PGs appear to stimulate resting macrophages and to inhibit activated cells. The stimulation of macrophagetumoricidal activity by PGs has been reported. The cytotoxic activity of lipopolysaccharide-activated macrophages was shown to be inhibited by the presence of indomethacin or aspirin in cultures of macrophages and tumor c e l l s . 157-16° The addition of PGE2 to these cultures restored antitumor activity. It has been suggested that PGs may affect tumoricidal activity differently depending upon the state of macrophage activation; PGE2 stimulated resident macrophages but inhibited the antitumor activity of activated macrophages. However, most reports concerning the effect of PGs on macrophage function indicate that PGE2 is inhibitory. Following the development of antitumor activity, macrophages in culture progressively lose the ability to kill neoplastic cells,z°,lSz-~ This loss has been attributed to an increase in PGE2. In a series of studies by Russell et al,19 it was shown that the levels of PGE2 increased rapidly after the addition of lipopolysaccharide to macrophage cultures. Nevertheless, despite the presence of PGE2 in sufficient quantity to inhibit antitumor activity, macrophages initially continued to destroy tumor cells. However, © Pearson Professional Ltd 1996

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a rapid loss in cytolytic activity occurred after 16-20 h of culture. The addition of indomethacin to these cultures prevented both the PGE2 synthesis and the loss of cytolytic activity. Kunkel et al21 have shown that PGEz inhibits the production of tumor necrosis factor. This may be an important autocrine regulation. Activated macrophages produce high levels of tumor necrosis factor and low levels of PGE2. As activation decays, PGE: levels increase, causing tumor necrosis factor production to decrease. Interferon-gamma is one of the major macrophage activating cytokines released by activated T-cells. It enhances macrophage Ia expression, both in vitro and in vivo ~6°-~62 and augments macrophage Fc receptor expression/63 cytotoxic activity,~64and tumoricidal activity.165,166Systematic administration of rMu tumor necrosis factor-a results in depressed synthesis of cyclooxygenase metabolites by peritoneal macrophages.2° The roles of cyclic AMP (cAMP) and growth factors in AA cascade products in intercellular signalling

PGs and LTs might modulate tumor growth by a cAMPmediated pathway. TM Young et al reported that the protein kinase A activity of the metastatic Lewis lung cells was readily stimulated by the lowest dose of PGE2 (25 ng/ml) and became further stimulated when the dose of PGE2 was increased to 50 ng/ml? 4'16z,16s In response to PGE2, both the metastatic and non-metastatic tumor cells generated an elevated cAMP response. The mechanism by which PGE2 stimulation of a cAMP response coupled to a protein kinase A response might result in increased tumor migration is unclear but could be associated with protein kinase A phosphorylation of microtubuleassociated proteins such that the microtubule assembly is inhibited. 1~9,17° Cowlen et al~66examined the effects of several fatty acid metabolites on the expression of the growth-regulated genes c-jun and jun-B in Syrian hamster embryo cells. Treatment of ceils with PGE2 resulted in the inhibition of epidermal growth factor (EGF)-induced DNA synthesis and c-jun mRNA accumulation, whereas PGE2 augmented EGF-stimulated jun-B mRNA and markedly stimulated jun-B accumulation in the absence of EGF. Treatment of cells with PGE2 resulted in rapid accumulation of cAMP, whereas PGF2~did not stimulate cAMP formation and did not alter EGF-stimulated DNA synthesis or accumulation of c-jun or jun-B mRNA. Inhibition of 5-lipoxygenase blocked EGF-dependent hydroxyoctadecadienoic acid formation and mitogenesis but did not affect EGFstimulated c-]un orjun-B mRNA accumulation. Hence the modulation of epidermal growth factor-dependent DNA synthesis by PGE2 may be associated with altered expression c-jun and jun-B in Syrian hamster embryo cells. In Prostaglandins, Leukotrienes and Essential FattyAcids (1996) 54, 3-16

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contrast, hydroxyoctadecadienoic acid appears to act downstream or divergent from c-jun andjun-B expression in the regulation of EGF-dependent DNA synthesis. Degradation of basement membrane AA metabolites have also been proposed to be involved in the degradation of basement membrane. The effect of AA metabolites on these processes may be indirect. 2° For example, collagenase, an enzyme that degrades collagen IV, is critical to tumor invasion in that it allows degradation of the basement membrane. 3,~67,~7~ Recently, it has been reported that metabolites of AA formed via both cyclooxygenase and lipoxygenase pathways are required for the production of collagenase W and that inhibition of these pathways renders human HT-1080 tumor cells non-invasive and non-metastatic. 53These studies indicate an important role for the metabolites of AA in the production of collagenase IV. Mechanisms of antitumor activity of PGs

Cyclopentenone PGs and alkylidene cyclopentenone PGs differ in their modes of action from other conventional PGs. They are actively incorporated into cells, transferred to the nuclei, 173-~75 inhibit cell cycle progression at the G~ phase and suppress replications of various viruses. Okuda-Ashitaka et al~TSreported that 1 ~tM PGD2 caused a rapid increase in the intracellular level of cAMP along with a 30% increase in [3H]thymidine incorporation. Deliconstantinos et aP 76 suggested that PGE2 and PGA2 promote a phase separation in microsomal membranes, thereby causing functional changes in the allosteric properties of integral enzymes located in the membranes. Cyclopentenone PGs have also been reported to synthesize heat shock proteins. ~72-~74 DISCUSSION

There are many reasons to believe that AA metabolism contributes to carcinogenesis in humans and that it is possible to modulate its involvement with cyclooxygenase and lipoxygenase inhibitors. The LTs and PGs are involved in tumor progression, induction of macrophages, angiogenesis, and tumor metastasis, and their inhibition may act synergistically with chemotherapy. However, it is not clear which PGs or LTs are responsible, where they are made, or how they act. Do the tumors make PGs and LTs that up-regulate the synthesis of growth factor receptors? Are similar effects exerted by PGs or LTs by invading macrophages or platelets? Do growing tumors release colony stimulating factors that activate macrophages to make PGs which inhibit proliferation of T-cells and the activity of natural killer cells? The biosynthesis of eicosanoids from PGs to LTs, inProstaglandins, Leukotrienes and Essential Fatty Acids (1996) 54, 3-16

cluding TXs prostacyclins, HETE and lipoxins, whether synthesized by the cyclooxygenase pathway or the lipoxygenase pathway, all depend on the availability of free AA. The control step for the production of free AA involves the activation of a phospholipase. Hence the inhibition of PLA2 activity might be more effective in cancer therapy. The release of AA from cell membranes appears to be the most crucial event in the cascading effects of AA through lipoxygenase and cyclooxygenase pathways. Blocking enzymatic reaction through one pathway may enhance the production of metabolites through the other pathway. Agents that block the activities of cyclooxygenase have been documented to result in the overproduction of LTs.At least two mechanisms could account for this. In one, AA would be shunted into the lipoxygenase pathway as a result of inhibition of cyclooxygenase, with a resultant increase in 12- and/or 15HETE synthesis. A second possibility is that these drugs could directly stimulate 12- and/or 15-HETE synthesis, w However, if one could inhibit the PLA2 step, one would have the potential of blocking both pathways. PLA2 are a family of esterases that hydrolyze the sn2-acyl ester bond in glycerophospholipid molecules? 77 These enzymes are generally calcium dependent and have been found both intra- and extracellularly, lzzlz8Inhibition of PLA2 decreases the release of the precursor fatty acid and thus the synthesis of all metabolites derived therefrom. It has been reported by Yamashita et al,z9 that membrane-associated PLA2 is closely related to the malignant potential of breast cancer. Since PLA2 is activated by calcium ions and calmodulin, it may be inhibited by drugs that reduce the availability of calcium ions. Indeed, the glucocorticoids, such as cortisone, have been suggested to act at the PLA2 step via a protein that inhibits PLA2 activity (lipocortin). ~s° Lister et al have reported that free fatty acids that were highly unsaturated were potent inhibitors of PLAa.183 Manoalide has also been reported to be an irreversible inhibitor of the extracellular PLA2. Manoalide is a natural product of sponge which has anti-inflammatory activity in vivo and inhibits phospholipase activity in vitro? TM Manoalide inhibits extracellular PLA2 activity in a time-dependent manner aided by calcium ions. Dennis has reported that both manoalide and its synthetic analog manoalogue were potent inhibitors of PG production in the micromolar range, is° Uteroglobin or blastokinin, a 15.8 kD steroid-dependent secretory protein was reported to be synthesized in the tracheobronchial, prostatic, seminal vesicular, and oviductal epithelia. This protein has potent anti-inflammatory and immunosuppressive properties? 77 It has been suggested that the immunomodulatory and anti-inflammatory properties of this protein may, at least in part, stem from its ability to inhibit PLA2 activity. Another PLA2 inhibitory protein with biological pro© Pearson Professional Ltd 1996

Cyclooxygenase and lipoxygenase inhibitors in cancer therapy

perties similar to t h o s e of u t e r o g l o b i n was r e p o r t e d to b e lipocortin I. Lipocortin I, in a d d i t i o n to h a v i n g PLA 2 i n h i b i t o r y activity, h a s also b e e n s h o w n to share antic h e m o t a c t i c effects in vitro w i t h u t e r o g l o b i n . 177 The i n h i b i t i o n of PG g e n e r a t i o n in vivo h a s b e e n c o r r e l a t e d with t h e i n h i b i t i o n of t h e release of AA from t h e p h o s p h o l i p i d s . Analogs of t h e n a t u r a l fatty acid p r e c u r sors c a n serve as c o m p e t i t i v e i n h i b i t o r s of t h e f o r m a t i o n of b o t h PGs a n d t h e p r o d u c t s of lipoxygenases. O n e s u c h i n h i b i t o r is t h e a c e t y l e n i c a n a l o g of AA, 5,8,11,14e i c o s a t e t r a y n o i c acid. The d i m e t h y l dienic a n a l o g of AA (DEDA) h a s b e e n r e p o r t e d to b e a p o t e n t i n h i b i t o r of PLA2Y ~ G o l d m a n et al~84 r e p o r t e d t h a t d i p h e n y l e n e i o d o n i u m , a specific i n h i b i t o r of NADPH oxidase, inhibits t h e activity of PLA2 in a d o s e - d e p e n d e n t manner. A n e w agent, CAI (NSC 609974), a s u b s t i t u t e d carboxyamido-triazole, has demonstrated antimetastatic activity in vitro a n d in v i v o Y 5-~s8 A l t h o u g h t h e m e c h a n i s m of a c t i o n of CAI r e m a i n s to b e fully elucidated, t h e effect of this m o l e c u l e a p p e a r s to o c c u r at t h e level of t h e p l a s m a m e m b r a n e a n d to involve interference w i t h signal t r a n s d u c t i o n p a t h w a y s involving c a l c i u m influx a n d t h e release of AA? s5-~88 A n a l t e r a t i o n in t h e release of AA a n d t h e p r o d u c t i o n of its m e t a b o l i t e s has b e e n i m p l i c a t e d in t h e m e c h a n i s m of a c t i o n of CAI. In conclusion, t h e literature to date suggests t h a t t h e i n h i b i t i o n of t h e p r o d u c t i o n of AA m e t a b o l i t e s t h r o u g h l i p o x y g e n a s e a n d c y c l o o x y g e n a s e p a t h w a y s plays a significant role in c a n c e r growth, p r o m o t i o n , a n d metastasis. Hence, it appears t h a t t h e role of PLA2, t h e e n z y m e inv o l v e d in t h e initiation of t h e entire cascade r e a c t i o n b y releasing AA m i g h t p l a y a n e v e n m o r e significant role in c a n c e r therapy. Therefore, a logical a p p r o a c h for c a n c e r t h e r a p y w o u l d b e to u s e i n h i b i t o r s of PLA 2 or to use a n a r a c h i d o n i c a n a l o g a l o n g w i t h s t a n d a r d c h e m o t h e r a p e u t i c drugs.

ACKNOWLEDGEMENTS The authors appreciate the support of NIH Grant # 5 R01 CAS0174-05 [Trimodality (X-Rays/Heat/Drugs): Mechanisms and Therapeutic Studies] for research in cancer control in this area.

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