Among the mechanisms of carcinogenesis are oncogene synthesis and expression, upregulation of cyclooxygenase, accelerated cell replication, failed apoptosis, viral activation, disruption of signaling pathways, autoimmunity, immunosuppression, angiogenesis and metastasis. All fall within the orbit of eicosanoids and the enzymes that synthesize them. Antidepressants may be of benefit in the prevention and treatment of cancer, as they inhibit the synthesis, antagonize the actions and accelerate the degradation of such eicosanoids as prostaglandins and thromboxanes.
Synthesized primarily by every cell membrane in the body, eicosanoids are ubiquitous in physiology and disease. Theessential fatty acid arachidonic acid (AA) is the primaryprecursor of such eicosanoids as prostaglandins(PGs), leukotrienes (LTs), thromboxanes (TXs) and lipoxins.
Since the identification of eicosanoids in1968 as potentially carcinogenic, an immense body of research has accumulated illuminating their ubiquitous role incancer. Isolation of isoforms of the PG-synthesizing enzymecyclooxygenase (COX) has stimulated interest in the potentialrole of selective COX-2 inhibitors in cancer treatment andprevention. the antiprostaglandin properties of antidepressants and their implications in cancer prevention and treatment have been neglected.
In 1968 Williams and coworkers reported high levels of PGs in the thyroid and plasma of patients with medullary cancer of thethyroid.[1] In 1976 Goodwin and coworkers reported increased synthesis of prostaglandin E2 (PGE2) in suppressor T-cells ofpatients with Hodgkin’s disease.[2] Numerous studies subsequently revealed elevated levels of PGsin solid tumors and in the immune cells and body fluids ofcancer patients.[3–12] Thousands of studies in animals and humans confirm the participation of eicosa- noids incarcinogenesis.[13–20]
PGs are involved in regulating the synthesis and expres- sion ofgenes and oncogenes. Genes and oncogenes in turn regulate suchPG-synthesizing enzymes as cyclo- oxygenase-2 (COX-2) andthe expression of PGs.[21–31]
The isolation of such isoforms of cyclooxygenase as COX-2 and the synthesis of selective COX-2 inhibitors havestimulated research into the expression of this isoform in cancer and its role in apoptosis. COX-2 overexpression converts procarcinogenstocarcinogens and inhibits apoptosis.
COX-2 is upregulated in such cancers as those of the head and neck, breast, lung, pancreas, bladder, cervix, prostate andmesothelium.32–45SuchPG-synthesis inhibitors as indomethacin andsulindac can induce regression of colon polyps in vivo andex vivo.[46] In population studies, chronic use of such PG-synthesis inhibitors as aspirin and ibuprofen has reduced the risk of colon cancer by as much as 50%.[47]
In 1983 Armato and Andreis reported that prostaglandinF1a and F2a intensely stimulate primary neonatal rat hepatocytes, F2a more powerfully stimulating DNA synth- esisthan arachidonic acid.[48]
In 1990 Goodlad and coworkersreported that the increase in gastric mucosal mass induced by misoprostol in the stomach of dogs is due to increased cell production. the increase in mucosal mass was the result of adramatic increase in the foveolar surface mucous cells.[49] Other studies have shown a para-doxical inhibitory effect of PGs on DNA synthesis.[50,51]
PGs and their synthesizing enzymes block apoptotic signals.such nonsteroidal anti-inflammatory compounds as sulindac andpiroxicam can induce apoptosis in normal and cancer cells.[52–57]Induction of PGs is essential if viruses, including the oncogenic, are to complete their replicative cycles.Indirectly, induction of PGs suppresses the antiviral activity of the immune system.[58,59]
Eicosanoids and their synthesizing enzymes are key factors in many signaling events. Disruptions of signaling pathways are incriminated in many cancers.[60–63]In a paradoxical counterpoint to immunosuppression, numerous autoimmune phenomena are reported in patients with cancer. Malignant tumors are diagnosed with increased frequency in patients with such auto-immune disorders as pemphigus, myasthenia gravis and the Eaton–Lambert syndrome. Apoptosis and PGs appear to play dual roles in autoimmunity and in cancer.[64–66]
Immunosuppression is both a cause and effect of cancer, avicious cycle.[67–70] Imai and his colleagues did an 11-year follow-up study to assess the level of naturalcytotoxic activity of such lymphocytes as natural killer (NK) cells and the incidence of cancer and death. their results showed that medium and high cytotoxic activity is associatedwith reduced cancer risk, and low activity is associated with increased cancer risk.[71]
Increase in PGs at the primary tumor focus may block surveillance by the immune system. PGs are potent suppressants of lymphocytes, and an increase in plasma PGs may contribute to a suppressive environment for lymphocyte function.
G.I. Deichman has shown that tumor progression in vivo isassociated with the appearance and selection of tumor cellswith a high level of antioxidant catabolizing activity and for the immediate release of prostaglandin E2 on contact with naturalkillers, macrophages and neu- trophils.
The expression of these phenotypes provides tumor cells with two mechanisms of local protection against effectors of innate and acquired antitumor activity. In primary viral carcinogenesis the selection of cells expressing these phenotypes begins within the latent period and can be completed by appearance of primary tumors.[72]
In 1983, Karmali and her coworkers reported that increased TX formation in human breast cancer specimensis associated with three clinical variables – tumor size, axillary lymph node metastases and distant metastases.the mechanisms in which PGs and TXs induce metastasis include induction of proteolyticenzyme production, neovascularization and subversion of the immune response.
The initiation of metastasis is thought to involve the adherence of circulating tumor cells to endothelial cells or to basement membranes. PGs and TXs play a role in adherence, with local TX concentrations possibly determining the sites of metastasis.[73–88]
The paraneoplastic syndrome includes a variety of neurological, hematological, metabolic cardiovascular and dermatological disorders. PGs are incriminated in many.[89–90]
Evidence from a variety of sources incriminates PGs in the pathogenesis of depression. Two-series PGs are elevated in the plasma,[91] spinal fluid,[92] and saliva of depressives,[93] and tranylcypromine directly lowers concentrations of the depressant prostaglandin D2 inthe brains of animals.[94] Infusion of prostacyclin, a two-series PG into patients withRaynaud’s disease as a vasodilator characteristically induces acutedepression.[95]
Horton’s 1966 report that PGs have powerful actions on thebrains of chicks and cats [96] stimulated intensive study of theactions of psychotropic drugs on PGs. Horrobin, Murphy and Wang and their coworkers showed that lithium carbonate inhibits prostaglandin E1 (PGE1).[97,98,99]
Recently, Chang showed that lithium decreases the turnover of arachidonate in various brain phospholipids.[100]
Lee showed that by inhibiting the mobilization of AA acid, antidepressants inhibit PGE2, with phenelzine (Nardil) exertinga more powerful antiprostaglandin effect than indomethacin.[101] Hong showed that tranylcypromine reduces the mobilization of archidonate,[102] while Horrobin and his coworkersshowed that such tricyclic antidepressants as imipramineand chlomipramine are weak PG agonists and powerful antagonists.[103]
Mtabaji and coworkers showed that tricyclicanti-depressants antagonize TXs.[104] Attempts to activate the primary prostaglandin degrading enzyme, 15-hydroxy- prostaglandindehydrogenase, failed until 1986, when Oi Mak and T.Chen showed that imipramine and amitriptyline have powerful activatory effects on this enzyme.[105]
Monoamine oxidase inhibitors, originally used in the treatmentof tuberculosis, have potent antiviral and immunoregulating properties. thus it is not surprising that one of them is effective in treating a neoplastic disease.
The disease is stage III and IV Hodgkin’s disease, the monoamine oxidase Matulane (procarbazine) part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen.
In ignoring the actions ofmonoamine oxidase inhibitors on PGs, the manufacturer states, ‘There is evidence that the drug may act by inhibition of protein, RNA and DNA synthesis.’
In the Ward Jones lecture given at Manchester University in1957, Sir Heneage Ogilvie commented,
‘I have slowly come to frame in my mind an aphorism that can never be stated as such,because no statistics can be advanced to support it: ‘‘The happy man never gets cancer’’ the instances where the first recognizable onset of cancer has followed almost immediately on some disaster, bereavement, the breakup of a relationship, a financial crisis, or an accident are so numerous that they suggest that some controlling force that has hitherto kept the outbreakyincheck has been removed.[106]
In 1998 B. W. J. H. Penninx and her coworkers at the National Institute of Aging provided compelling support for Ogilvie’s hypothesis: chronically depressed people over theage of 70 are 88% more likely to develop cancer and twice as likely to die of it than their cheerful peers.[107]
In interstices between cell membrane phospholipids and genes,membrane phospholipids and organelles, genes and enzymes, genes and proteins, PGs induce cancer. the places where PG-synthesizing enzymes convert AA acidor phospholipids to PGs are possible sites of action ofantidepressants.
The ability of antidepressantsto alleviate or remit such autoimmune disorders as migraine, rheumatoid arthritis, asthma and multiple sclerosis strengthens the case for their potentialvalue in cancer.[108]
Depression incancer patients may be more an antecedent than a consequence of the disease.[121–124]
As depression lowers the threshold for stress and reduces compliance with adjuvant chemotherapy,[125] antidepres- sants may be of value inenhancing compliance. it would be surprising if the antiviral and immunostimulating properties alone of antidepressants did not lend themselves to cancer prevention and treatment.[112–120]
Other than the finding that lithium inhibits various phospholipases,[100] the actions of psychotropic agents on the arachidonic cascade has stimulated little recent research. the actions of antidepressants on such aspects of carcinogenesis as apoptosis, gene activation and suppression and the expression of COX and other enzymes appear to be fertile areas for basic and applied pharmacology.
The antiprostaglandin, antiviral and immunopotentiating properties of lithium carbonate suggest that it too is worthy of investigation in the prevention and treatment of cancer beyond that of its protective effects onhematopoeisis during chemotherapy.[126–134]
As the response to antidepressants is highly specific, many patients require multiple trials before their depression responds. Some subjects are refractory to all antidepressants and many relapse due to tachyphylaxis.[135]
PGs are capable of paradoxical pro-carcinogenic and anti-carcinogenic actions.[136-137].
Maintaining an index of suspicion, close clinical observation and limiting the duration of drug trials can mitigate such paradox.
1. Williams E. D., Karim S. M. M., Sandler M. Prostaglandin secretion bymedullary carcinoma of the thyroid. Lancet 1968;1: 22–23.
2. Goodwin J. S., Murphy S., Bankhurst A. D., et al. Prostaglandin-producing suppressor cells in Hodgkin’s disease. new Engl J Med1977; 297: 963–968.
3. Bennett A., Carter R. L., Stamford, I. F., Tanner N. S. B.Prostaglandin-like material extracted from squamous carcinomasof the head and neck. Br J Cancer 1980; 41:204–209.
4. Karmali R. A., Welt S., Thaler H. T., Lefevre F. Prostaglandins inbreast cancer: relationship to disease stage and hormone status. Br JCancer 1983; 48: 689–696.
5. Cooper C., Jones H. G., Weller R. O., Walker V. Production ofprostaglandins and thromboxane by isolated cells fromintracranial tumors. J Neurol Neurosurg Psych 1984; 47:579–584.
6. Amlot P. L., Chivers A., Heizelmann D., Youlten L. J. F. Increasedprostaglandin synthesis in Hodgkin’s disease: a lymphocyte-monocyte interaction. Adv Prost Thromb Res 1980; 6: 529–532.
7. Plescia O. J., Smith A. H., Grinwich K. Subversion of immune systemby tumor cells and role of prostaglandins. Proc Nat Acad Sci 1975;72(5): 1848–1851.
8. Balch C. M., Dougherty P. A., Tilden A. B. Excessiveprostaglandin E2 production by suppressor monocytes in head andneck cancer patients. Ann Surg 1982; 645–650.
9. Cameron D. J., Stromberg B. V. the ability of macrophages from headand neck cancer patients to kill tumor cells: effects of prostaglandininhibitors on cytotoxicity. Cancer 1984; 54(11):2403–2408.
10. Fiedler L., Zahradnik H. P., Schlegel G. Perioperative behavior ofprostaglandin E2 and 13,14 dihydro-15-keto-PGF2a in serum ofbronchial carcinoma patients. Adv Prost Thromb Res 1980;585–586.
11. Harvey P. R. C., Kimura L. H., Cripps C., Hokama Y. Distribution ofprostaglandins B, E and F series in plasma of cancer patients. J Med1981; 12(6): 427–432.
12. Bennett A., Berstock D. A., Harris M., Raja B., Rowe D. J. F.Prostaglandins and their relationship to malignant and benign breasttumors. Adv Prost Thromb Res 1980; 4: 595–600.
13. Karmali R. A., Sarkar N. H., Emerson W., good R. A.Prostaglandin regulation of murine mammary tumor virus production: abasis for some of the glucocorticoid and prolactin actions on mammarytumor cell cultures. Prosta Leuk Med1982; 9: 641–655.
14. Karmali R. A. Review: prostaglandins and cancer. ProstaglandinsMed 1980; 5: 11–28.
15. Bennett A., Houghton J., Leaper D. J., Stamford I. F. Cancergrowth, response to treatment and survival time in mice:beneficial effect of the prostaglandin synthesis inhibitorflurbiprofen. Prostaglandins 1979; 17(2): 179–191.
16. Popescu C. Z. the role of prostaglandins in the development ofmalignant melanoma in hamsters. Prosta Med 1981; 7: 321–325.
17. Cohen L. A., Karmali R. A. Endogenous prostaglandin production byestablished cultures of neoplastic rat mammary epithelial cells. In Vitro1984; 20(2): 119–126.
18. Lupulescu A. Enhancement of carcinogenesis by prostaglandins.Nature 1978; 272(13): 634–636.
19. Karmali R. A., Horrobin D. F., Ghayur T., Manku M. S., CunnaneT. C., et al. Influence of agents which modulatethromboxane A2 synthesis or action on R 3230AC mammarycarcinoma. Cancer Letters 1978; 5: 205–208. Prostaglandins, Leukotrienes and Essential Fatty Acids (2001) 65(5&6), 233^239
20. Quia L., Kozoni V., Tsioulias G. J., Koutsos M. I., Hanif R. Selectedeicosanoids increase the proliferation of human colon carcinoma cell linesand mouse monocytes in vivo. Biochem Biophys Acta 1995; 1258(2):215–223.
21. Hermann C., Block C., Geisen C., Haas K., Weber C., et al.Sulindac sulfide inhibits Ras signaling. Oncogene 1998; 17(14):1769–1776.
22. Ramsay R. G., Friend A., Vizantios Y., Freeman R., Sicurella C., et al.Cyclooxygenase-2, a colorectal cancer nonsteroidal anti- inflammatorydrug target, is regulated by c-MYB. Cancer Res2000; 60(7): 1805–1809.
23. Fitzgerald J., Edietz T. J., Hughes-Fulford M. ProstaglandinE2-induced up-regulation of c-fos messenger ribonucleic acidis primarily mediated by 3’,5’-cyclic adenosine monophosphate inMC3T3-E1 osteoblasts. Endocrinology 2000; 141(1):291–298.
24. Honn K. V., Dunn J. R., Morgan L. R., Bienkowski M., Marnett L. J.Inhibition of DNA synthesis in Harding–Passey melanoma cells byprostaglandins A1 and A2: comparison with chemotherapeutic agents.Biochem Biophys Res Comm 1979;87(3): 795–801.
25. Hughes-Wiley M. H., Feingold K. R., Grunfeld C., Quesney- Huneeus V.,Wu J. M. Evidence for c-AMP independent inhibition of S-phase DNAby prostaglandins. J Biol Chem 1983;258(1): 491–496.
26. Hughes-Fulford M., Wu J., Kato T., et al. Inhibition of DNA synthesisand cell cycle by prostaglandins independent of cyclic AMP. AdvProstaglandin Thromboxane Leukot Res 1985; 15:401–404.
27. Hughes-Fulford M. Prostaglandin regulation of gene expression andgrowth in normal and malignant tissues. Adv Exp Med Biol1997; 400A: 269–278.
28. Sinha D., Addya S., Murer E., Boden G. 15-Deoxy-delta (12,14)prostaglandin J2: a putative endogenous promoter of adipogenesissuppresses the ob gene. Metabolism 1999; 48(6):786–791.
29. Choudry M. A., Uddin S., Sayeed M. M. Prostaglandin E2modulation of p59fyntyrosine kinase in T-lymphocytes during sepsis. JImmunol 1998; 160(2): 929–935.
30. Kim J. S., Chae H. D., Joh T. H., et al. Stimulation of human DBHgene expression by prostaglandin E2 in human neuroblastomaSK-N-BE(2)C cells. J Mol Neurosci 1997; 9: 143–150.
31. Pinelli E., Poux N., Garren L., et al., Activation of mitogen- activatedprotein kinase by fumonisin B(1) stimulates cPLA(2) phosphorylation,the arachidonic acid cascade and CAMPproduction. Carcinogenesis 1999; 20: 1683–1688.
32. Sheng H., Williams C. S., Shao J., Liang P., Dubois R. N.,Beauchamp R. D. Induction of cyclooxygenase-2 by activatedHa-ras oncogene in Rat-1 fibroblasts and the role of mutated proteinkinase pathway. J Biol Chem 1998; 273(34):22121–22427.
33. Emond V., Fortier M. A., Murphy B. D., Lambert R. D.Prostaglandin E2 regulates both interleukin-2 and granulocyte-macrophage colony-stimulating factor gene expression in bovinelymphocytes. Biol Reprod 1998; 568(1): 143–151.
34. Gilhooly E. M., Rose D. P. the association between a mutated rasgene and cyclooxygenase-2 expression in human breast cancer cell lines.Int J Oncol 1999; 15(2): 267–270.
35. William C. S., Mann M., Dubois R. N. the role ofcyclooxygenases in inflammation, cancer and development.Oncogene 1999; 18(55): 7908–7916.
36. Fosslien E. Molecular pathology of cyclooxygenase-2 inneoplasia. Ann Clin Lab Sci 2000; 30(1): 3–21. Review: antidepressants, eicosanoids and cancer 237
37. Chan G., Boyle J. O., Yang E. K., Zhang F., Sacks P. G., et al.Cyclooxygenase-2 expression is upregulated in squamous cellcarcinoma of the head and neck. Cancer Res 1999; 59(5):991–994.
38. Achiwa H., Yatabe Y., Hida T., Kuroishi T., Kozaki K., et al.Prognostic significance of elevated cyclooxygenase 2 expressionin primary, resected lung adenocarcinomas. Clin Cancer Res 1999;5(5): 1001–1005.
39. Watkins D. N., Lenzo J. C., Segal A., Garlepp M. J., Thompson P. J.Expression and localization of cyclooxygenase isoforms in non- smallcell lung cancer. Eur Resp J 1999; 14(2): 412–418.
40. Molina M. A., Sitja-Arnau M., Lemoine M. G., Frazier M. L.,Sinicrope F. A. Increased cyclooxygenase-2 expression in humanpancreatic carcinomas and cell lines: growth inhibition by nonsteroidalanti-inflammatory drugs. Cancer Res 1999;59(17): 4356–4362.
41. Sawaoka H., Kawano S., Tsuji S., Tsugi M., Sun W., et al.Helicobacter pylori infection induces cyclooxygenase-2 expressionin human gastric mucosa. Prostaglandins Leukot Essent Fatty Acids1998; 59(5): 313–316.
42. Murata H., Kawano S., Tsuji S., Tsuji M., Sawaoka H., et al.Cyclooxygenase-2 overexpression enhances lymphatic invasion andmetastasis in human gastric carcinoma. Am J Gastroenterol1999; 94(2): 451–455.
43. Yoshimura R., Sano H., Masuda C., Kawamura M., Tsubouchi Y.Expression of cyclooxygenase-2 in prostatic carcinoma. Cancer2000; 89(3): 589–596.
44. Marrogi A., Pass H. I., Khan M., Metheny-Barlow I. J., Harris C.C., Gerwin B. I. Human mesothelioma samples overexpress bothcyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (NOS2):in vitro antiproliferative effects of a COX-2 inhibitor.Cancer Res 2000; 60(14): 3696–3700.
45. Taketo M. M. Cyclooxygenase-2 inhibitors in tumorigenesis(part 1). J Natl Cancer Inst 1998; 90(20): 1529–1536.
46. Al-Saleem T. Skin cancers in xeroderma pigmentosum: response toindomethacin and steroids. Lancet 1980; 264–266.
47. Thun M. J., Namboordiri M. M., Heath C. W. Jr. Aspirin use andreduced risk of fatal colon cancer. N Engl J Med 1991; 325:1593–1956.
48. Armato U., Andreis P. G. Prostaglandins of the F series areextremely powerful growth factors for primary neonatal rathepatocytes. Life Sci 1983; 33: 1745–1755.
49. Goodlad R. A., Madgwick A. J., Moffatt M. R., et al. Prostaglandinsand the dog stomach: effects of misoprostol on the proportion ofmucosa to muscle and on the proportion of different epithelial typecells. Digestion 1990; 45: 212–216.
50. Nilsson J., Olsson A. G. Prostaglandin E1 inhibits DNA synthesisin arterial smooth muscle cells stimulated with platelet-derived growthfactor. Atherosclerosis 1984; 53: 77–82.
51. Smith D. L., Willis A. L., Mahmud I. Eicosanoid effects on cellproliferation in vitro: relevance to atherosclerosis. Prosta LeukMed 1984; 16: 1–10.
52. Waddell W. R. Stimulation of apoptosis by sulindac andpiroxicam. Clin Sci (Colch) 1998; 95(3): 385–388.
53. Lim J. T., Piazza G. A., Han E. K., et al. Sulindac derivatives inhibitgrowth and induce apoptosis in human prostate cancer cell lines.Biochem Pharmacol 1999; 58: 1097–1107.
54. Kusuhara H., Matsuyuki H., Matsuura M., Imayoshi T.,Okumoto T., et al. Induction of apoptotic DNA fragmentation bynonsteoidal anti-inflammatory drugs in cultured rat gastric mucosalcells. Eur J Pharmacol 1998; 360(2–3): 273–280.
55. Dittmann K. H., Mayer C., Rodemann H. P., et al. MK-886, aleukotriene biosynthesis inhibitor induces antiproliferative effects andapoptosis in HL-60 cells. Leuk Res 1998; 22: 49–53.
56. Kawamura T., Horie S., Maruyama T., Akira T., Imagawa T.,Prostaglandin E1 transported into cells blocks the apoptotic signalsinduced by nerve growth factor deprivation. JNeurochem 1999; 72(5): 1907–1914.
57. Baliff B. A., Mincek N. V., Barratt J. T., et al. Interactionof cyclooxygenases with an apoptosis- and autoimmunity-associated protein. Proc Natl Acad Sci USA 1996; 93:5544–5549.
58. Dore-Duffy P. Differential effect of prostaglandins and otherproducts of arachidonic acid metabolism on measles virusreplication in vero cells. Prosta Leuk Med 1982; 8:73–82.
59. Wahl L. M., Corcoran M. L., Pyle S. W., et al. Human immunodeficiencyvirus glycoprotein (gp 120) induction of monocyte arachidonic acid andinterleukin 1. Proc Natl Acad Sci USA 1989; 86: 621–625.
60. Schaad N. C., Magistretti P. J., Schorderet M. Prostanoids andtheir role in cell-cell interactions in the central nervous system.Neurochem Int 1991; 18(3): 303–322.
61. Villaneuva A., Garcia C., Paules A. B., Vicente M., Megias M.Disruption of the antiproliferative TGF-b signaling pathways in humanpancreatic cancer cells. Oncogene 1998; 17(15):1969–1978.
62. Di Battista J. A., Martel-Pelletier J., Pelletier J. Suppression of tumornecrosis factor (TNFa) gene expression by prostaglandin E2. Role of earlygrowth response protein-1 (Egr-1). Osteoarthritis Cartilage 1999; 7(4):395–398.
63. Moreno J. J. Regulation of arachidonic acid release and prostaglandinformation cell-to-cell adhesive interactions in wound repair. PflugersArch 1997; 433: 351–356.
64. Houssiau F. A., Kirkove C., Asherson R. A., Hughes G. R. V.,Timothy A. R. Malignant lymphoma in systemic rheumatic diseases. A report of five cases. Clin Exp Rheum 1991; 9:515–518.
65. Sela O., Shoenfeld Y. Cancer and autoimmune diseases. SeminArthritis Rheum 1988; 18: 77–87.
66. Isomaki H. A., Hakulinen T., Joutsenlahti U. Excess risk oflymphomas, leukemia and myeloma in patientswith rheumatoid arthritis. J Chronic Dis 1978; 31:691–696.
67. Young M. R., Dizer M. Enhancement of immune function and tumorgrowth inhibition by antibodies against prostaglandin E2. Immunol Comm1983; 12(1): 11–23.
68. Leung K. H., Mihich E. Prostaglandin modulation of development ofcell-mediated immunity in culture. Nature1980; 288: 597–600.
69. Dilman V. R. Metabolic immunosuppression which increases the riskof cancer. Lancet 1977; ii: 1207–1210.
70. Buda J. A., Suciu-Foca N., Blomain E., McManus S., Reemtsma K.Impaired cell-mediated immunity in patients with cancer. J SurgOnc 1975; 7: 525–529.
71. Imai K., Matsuyama S., Miyake S., Suga K., Nakachi K. Naturalcytotoxic activity of peripheral-blood lymphocytes and cancer incidence:an 11-year follow up study of a general population. Lancet 2000; 356:1795–1799.
72. Deichman G. I. Natural selection and early changes ofphenotype of tumor cells in vivo: acquisition of new defensemechanisms. Biochemistry (Mosc) 2000; 65(1): 78–94.
73. Peterson H. I. Tumor angiogenesis inhibition by prosta-glandin synthase inhibitors. Anticancer Research 1986; 6:251–254.
74. Chiarugi V., Magnelli L., Gallo O. COX-2, iNOS and p53 as playmakersof tumor angiogenesis (review). Int J Mol Med 1998;2(6): 714–720. Prostaglandins, Leukotrienes and Essential Fatty Acids (2001) 75. Damtew B., Spagnuolo P. J. Tumor cell-endothelial cell interactions:evidence for roles for lipoxygenase products of arachidonic acid inmetastasis. Prostaglandins Leukot Essential Fatty Acids 1978; 56(4):295–300.
76. Fulton A. M. Inhibition of experimental metastasis withindomethacin: role of macrophages and natural killer cells.Prostaglandins 1988; 35(3): 13–42.
77. Tisdale M. J. Role of prostaglandins in metastatic dissemination ofcancer: minireview on cancer research. Expl Cell Biol 1983;51: 250–256.
78. Daniel T. O., Liu H., Morrow J. D., Crews B. C., Marnett L. J.Thromboxane A2 is a mediator of cyclooxygenase dependentendothelial migration and angiogenesis. Cancer Res 1999;59(18): 4574–4577.
79. Fulton A. M. Interactions of natural effector cells andprostaglandins in the control of metastasis. JNCI 1987; 78:735–740.
80. Stringfellow D., Fitzpatrick F. Prostaglandin D2 controls pulmonarymetastasis of malignant melanoma cells. Nature1979; 282: 76–78.
81. Nanji A. A. Thromboxane synthase and organ preference formetastases. new Eng J Med 1979; 138–139.
82. Fantone J. C., Elgas L. J., Weinberger L., Varani J. Modulation of tumorcell adherence by prostaglandins. Oncology 1983; 40:421–426.
83. Honn K. V., Cicone B., Skoff A. Prostacyclin: a potentantimetastatic agent. Science 1981; 212: 1270–1272.
84. Duffy C. P., Elliott C., O’Connor R. A., Heenan M. M., Coyle S., etal. Enhancement of chemotherapeutic drug toxicity to human tumorcells in vitro by a subset of non-steroidal anti- inflammatory drugs(NSAIDs). Eur J Cancer 1998; 34(8):1250–1259.
85. Greaves K., Ibbotson K. J., Atkins D., Martin T. J. Prostaglandins asmediators of bone resorption in renal and breast tumors. Clin Sci 1980;58: 201–210.
86. Kaneti J., Thomson M. P., Reid C. R. Prostaglandin E2 affects thetumor immune response in prostatic cancer. J Urol 1981; 126:65–70.
87. Lala P. K., Elkashab M., Kerbel R. S. W., Parhar R. S. Cure of humanmelanoma lung metastases in nude mice with chronic indomethacintherapy combined with multiple rounds of IL-2: characteristics of killercells generated in situ. Int Immunol1990; 2(12): 1149–1158.
88. Rosenberg L., Palmer J. R., Zauber A. G., Warshauer M. E., Stolley P.D., et al. A hypothesis: non-steroidal anti-inflammatory drugs reduce theincidence of large-bowel cancer. J Natl Cancer Inst1991; 83: 355–358.
89. Minna J. D., Bunn P. A. Jr. Paraneoplastic syndromes.In: Devita V. T. et al., eds. Philadelphia: Lippincott, Principles andPractices of Oncology. 1982; 1476–1517.
90. Grunwald G. B., Simmonds M. A., Klein R., Kornguth S. E.Autoimmune basis for visual paraneoplastic syndrome in patientswith small-cell lung carcinoma. Lancet 1985; 1:658–661.
91. Lieb J., Karmali R., Horrobin D. Elevated levels of prostaglandinE2 and thromboxane B2 in depression. Prostaglandins LeukotMed 1983; 10: 361–367.
92. Linnoila M., Whorton A. R., Rubinow D. K. CSF prostaglandin levelsin depressed and schizophrenic patients. Arch Gen Psychiatry 1983;40: 405–406.
93. Ohishi K., Ueno R., Nishino S. Increased level of salivaryprostaglandins in patients with major depression. Biol Psychiatry1988; 23: 326–334. Prostaglandins, Leukotrienes and Essential Fatty Acids (2001) 65(5&6), 233^239
94. Ellis E. F., Rosenblum W. I., Birkle D. L. Lowering of brain levels ofthe depressant prostaglandin D2 by the antidepressant tranylcypromine.Biochem Pharmacol 1982; 31: 1783–1784.
95. Ansell D., Belch J. J., Forbes C. D. Depression and prostacyclininfusion. Lancet 1986; 2: 1203–1205.
96. Horton E. W. Actions of prostaglandins E1, E2 and E3 on the centralnervous system. Brit J Pharmacol 1964: 22: 189–192.
97. Horrobin D. F., Mtabaji J. P., Manku M. S., et al. Lithium as a regulatorof hormone-stimulated prostaglandin synthesis. In:Johnson F. N., Johnson F. Lithium in Medical Practice. Baltimore, MD:University Park Press, 1978; 243–263.
98. Murphy D. L., Donnelly C., Moskowitz J. Inhibition by lithium ofprostaglandin E1 and norepinephrine effects on cyclicadenosine monophosphate production in human platelets. ClinPharm Therap 1973; 15(5): 810–815.
99. Wang Y-C., Pandey G. M., Mendels J., Frazier A. Effect of lithium onprostaglandin E1 stimulated adenyl cyclase activity of human platelets.Biochem Pharmacol 1974; 23: 845–855.
100. Chang M. C. J., Grange E., Rabin O., et al. Lithium decreasesturnover of arachidonate in several brain phospholipids.Neurosci Lett 1996; 230: 171–174.101. Lee R. E. the influence of psychotropic drugs on prostaglandinbiosynthesis. Prostaglandins 1974; 51: 63–68.
102. Hong S. H., Carty T., Deykin D. Tranylcypromine and 15-hydroperoxyarachidonate effect arachidonic acid release in additionto inhibition of prostacyclin synthesis in calf aortic endothelial cells. JBiol Chem 1980; 2455(20): 9538–9540.
103. Manku M. S., Horrobin D. F. Chloroquine, quinine, procaine,quinidine and clomipramine are prostaglandin agonists andantagonists. Prostaglandins 1976; 12: 789–801.
104. Mtabaji J. P., Manku M. S., Horrobin D. F. Actions of the tricyclicantidepressant clomipramine on responses to pressor agents:interactions with prostaglandin E2. Prostaglandins 1977; 14:125–132.
105. Mak O., Chen S. Effects of two antidepressant drugs-imipramine andamitriptyline on the enzyme activity of 15-hydroxyprostaglandin dehydrogenase purified from brain, lung, liverand kidney of mouse. Prog Lipid Res 1986; 25: 153–155.
106. Ogilvie H. the Human Heritage (the Ward Jones lecture,Manchester University). Lancet, July 6th, 1957.
107. Penninx B. W., Guralnik J. M., Pahor M., Ferruci L., Cerhan J. R. et al.Chronically depressed mood and cancer risk in older persons. J NatlCancer Inst 1998; 90(24): 1888–1893.
108. Lieb J. Remission of rheumatoid arthritis and other disorders ofimmunity in patients taking monoamine oxidase inhibitors. Int JImmunopharmacol 1983; 5: 353–357.
109. Magni G., Conlon P., Arsie D. Tricyclic antidepressants in thetreatment of cancer pain: a review. Pharmacopsychiat 1987; 20:160–164.
110. Botney M., Fields H. L. Amitriptyline potentiates morphine analgesiaby direct action on the central nervous system. Ann Neurol 1983;13(2): 160–164.
111. Breitbart W. Psychotropic adjuvant analgesics for pain in cancerand AIDS. Psychooncology 1998; 7(4): 333–345.
112. Lieb J. Invisible antivirals. Int J Immunopharmacol 1994; 16: 1–5.
113. Rosenthal S. H. Does phenelzine relieve aphthous ulcers of the mouth?new Engl J Med 1984; 311: 1442.
114. Rosenthal S. H., Fitch W. P. the antiherpetic effect of phenelzine.J Clin Psychopharmacol 1987; 7: 119.
115. Lofft J. MAO inhibitors. Psychiat Times 1985; 11.
116. Ali B. H., Bartlet A. L. Inhibition of monoamine oxidase inchickens and ducklings by a microbial metabolite of furazolidone.Q J Exp Physiol 1982; 67: 69–79. Review: antidepressants, eicosanoids and cancer 239 117. Zilberstein D., Dwyer D. M. Antidepressants cause lethaldisruption of membrane function in the human protozoan parasiteLeishmania. Science 1984;118.Weinbach E. C., Costa J. L., Wieder S. C. Antidepressant drugssuppress growth of the human pathogenic protozoan Giardia lamblia.Res Commun Chem Pathol Pharmacol 1985; 47:145–148.
119. Bitonti A. J., Sjoerdsma A., McCann P. P., et al. Reversal ofchloroquine resistance in malaria parasite Plasmodiumfalciparum by desipramine. Science 1988; 242: 1301–1303.
120. Salama A., Facer C. A. Desipramine reversal of chloroquineresistance in wild isolates of Plasmodium falciparum. Lancet1990; 335: 164–165.
121. Fulton C. the prevalence and detection of psychiatric morbidity inpatients with metastatic breast cancer. Eur J Cancer Care(Engl) 1998; 7(4): 232–239.122. Bottomley A. Depression in cancer patients: a literature review.Eur J Cancer Care (Engl)1998; 7(3): 181–191.
123. Pirl W. F., Roth A. J. Diagnosis and treatment of depression in cancerpatients. Oncology (Huntingt) 1999; 13(9): 1293–1301.
124. Kugaya A., Akechi T., Nakano T., Okamura H., Shima Y., et al.Successful antidepressant treatment for five terminally ill cancerpatients with major depression Suicidal ideation and a desire for death.Support Care Cancer 1999; 7(6): 432–436.
125. Colleoni M., Mandala M., Perruzotti G., Robertson C., Bredart A., et al.Depression and degree of acceptance of adjuvant cytotoxic drugs. Lancet2000; 356: 1326–1327.
126. Lieb J. Remission of recurrent herpes during therapy with lithium.N Eng J Med 1979; 301: 942.
127. Amsterdam J. D., Maislin G., Rybakowski J. A possible antiviral actionof lithium carbonate in herpes simplex virus infections. Biol Psychiatry1990; 27: 447–453.
128. Lieb J. Remission of herpes virus infection and immunopotentiationwith lithium carbonate: inhibition of prostaglandin E1 may explain its antiviral, immunopotentiating andantimanic properties. Biol Psychiatry 1981; 695–698.
129. Lieb J. Lithium and immune function. Med Hypotheses 1987; 23:73–93.Skinner G. R., Hartley C., Buchan A., et al. the effect of lithium chlorideon the replication of herpes simplex virus. Med Microbiol Immunol1980; 168: 139–148.
130. Hansell N. Manic illness presenting with physical symptoms.Am J Psychiatry 1996; 147: 11.Cohen Y., Chetrit A., Cohen Y., Sirota P., Modam B. Cancermorbidity in psychiatric patients: influence of lithium carbonatetreatment. Med Oncol 1998; 15(1): 32–36.
131. Ravischandran D., Cooper A., Johnson C. D. Effect of lithiumgamma-linolenate on the growth of experimental human pancreaticcarcinoma. Br J Surg 85(9): 1201–1205.
132. Steinherz P. G., Rosen G., Giavini F., Wang Y., Miller D. R. the effectof lithium carbonate on leukopenia after chemotherapy. J Ped PharmTher 1980; 96(5): 923–927.
133. Lieb J., Balter A. Antidepressant tachyphylaxis. Med Hypoth1984; 15: 279–291.
134. Fukushima M., Kato M. Antitumor marine icosanoids:clavulones and punaglandins. Adv Prost Thromb and Leuk Res1985; 15: 415–418.
135. Fukushima M., Kato M. Antineoplastic prostaglandin: antitumor effect of PGA and PGJ derivatives. In: Thaler-Dao H., et al. eds. Icosanoids andcancer. new York: Raven Press, 275–278.
136. Cotterchio M., Kreiger N., Darlington G., Steingart A.Antidepressant medication use and breast cancer risk. Am JEpidemiol 2000; 151(10): 951–957.
137. Damluji N. F., Ferguson J. M. Paradoxical worsening ofdepressive symptomatology caused by antidepressants. J ClinPsychopharm 1988; 8(5): 347–349.