It is generally understood that the metastasis of tumor cells is a critical event in the natural history and spread of cancer The spread of the tumor often places it beyond surgical treatment and results in a drastically worsened prognosis for the patient. Current concepts suggest that metastasis is a complex, multistep process (Fidler, I. J. et. al., Adv. Cancer Res., 28: 149-250, 1978). However, invasion through basement membrane is an essential step in the process by which tumor cells form new lesions and this may involve a common mechanism for many tumor cells. Basement membranes (Martin, G. R., et. al., Ann. Rev. Cell Biol., 3: 57-85, 1987), are the extracellular structures surrounding most epithelial tissues, nerves and muscle and lining most blood and lymph vessels. Collagen IV, laminin and a large heparan sulfate proteoglycan are major components of basement membranes. Basement membranes represent significant barriers to most cells, but malignant tumor cells can penetrate them. This is believed to require degradation by specific proteolytic enzymes (Liotta, L. A., Am. J. Pathology, 117: 335-348, 1986), (Terranova, V. P. et. al., J. Natl. Cancer Inst., 77: 311-316, 1986). Because the basement membranes in all tissues have the same components, (Martin, G. R., et. al., Ann. Rev. Cell Biol., 3: 57-85, 1987), it is possible that similar mechanisms are employed by many malignant tumor cells in invading basement membranes, although this has not been shown directly. The degradation of the collagen IV network may be the critical step, (Liotta, L. A., Am. J. Pathology, 117: 335-348, 1986), (Terranova, V. P. et al., J. Natl. Cancer Inst., 77: 311-316, 1986) and it may be possible that collagenase IV is needed to do this. However, this is uncertain since other proteases includinq gelatinase, stromelysin, and elastase are able to degrade the collagen IV monomer under in vitro conditions (Murphy, G. et. al., Biochem. Biophys. Acta, 831: 49-58, 1985).
Collagenase IV is secreted in an inactive form. Activation of the enzyme is achieved via plasminogen activator and plasmin. Inhibition of either enzyme prevents malignant tumor cells from being invasive (Reich, R. et. al., Cancer Res. 48: 3307-3312, 1988). A high production of plasminogen activator is frequently observed with malignant cells (Dano, et. al., Adv. Can. Res. 44: 139-266, 1985).
Laminin and the protein of the heparan sulfate proteoglycan are susceptible to a variety of proteolytic enzymes. Degradation of the heparan sulfate chains requires a heparanase, and inhibitors of this enzyme have been shown to be antimetastatic in experimental studies (Nakajima, M., et. al., Cancer Research, 47: 4869-4876, 1987).
Motility factors and tissue chemotactic factors can stimulate the movement of malignant tumor cells and have been implicated in the organ specific metastasis of certain tumor cells (Hujanen, E. S. et. al., Cancer Research, 45: 3517-3521, 1985). Matrix proteins such as laminin have both chemotactic and heptotactic activity and might be expected to accelerate the movement of malignant tumor cells (McCarthy, J. B. et. al., Cancer Metastasis Rev., 4: 125-152, 1985). In vitro assays of tumor cell invasiveness often employ chemoattractants to increase the migration of the tumor cells (Albini, A. et. al., Cancer Research, 47: 3239-3245, 1987). Chemoattractants may have a significant role in tumor cell metastasis.
Hematogenous tumor metastasis is thought to be mediated in part by alternations in vascular integrity and interactions with platelets. Arachidonic acid metabolites, i.e., prostacyclin, thromaoxane A.sub.2 and leukotrienes are powerful modulators of vascular integrity, tone and platelet aggregation and may be involved in the development of tumor growth and metastasis. There is evidence of a correlation between tissue levels of leukotriene C.sub.4 levels and vasogenic edema surrounding brain tumors, K. C. Black, et al. ANNALS OF NEUROLOGY 19(6):592-595 (1986). Honn, et al., demonstrated that selective inhibition of thromboxane synthetase, as well as pretreatment with exogenous prostacyclin significantly decreased hematogenous metastases in animal models. SCIENCE 212:1270(1981); ADV.PROSTAGLANDIN, THROMBOXANE, LEUKOTRIENE RES.12:313 (1983); BIOCHEM. BIOPHYS. RES. COMMUN. 102:1122(1981). Ketoconazole, an antifungal agent which inhibits both the thromboxane synthetase and 5-lipoxygenase metabolic pathways significantly reduced metastasis of B16-F10 murine melanoma cells in mice, P. A. Wardone, et. al, J. SURG. RES. 44 (4): 425-429 (1988). When human PC-3 cells derived from a metastatic prostate adenocarcinoma were incubated with eicosatetraynoic acid, an in vitro inhibitor of arachidonic acid metabolism (cyclooxygenase and lipoxygenase), DNA synthesis was supressed, K. M. Anderson, et al., THE PROSTATE 12:3-12 (1988).
Cyclooxygenase inhibitors have been used as nonsteroidal antiinflammatory agents (NSAID's) and analgesics. Mixed cyclooxygenase/lipoxygenase inhibitors such as benoxaprofen have been used for the same purposes. Both groups of drugs have exhibited undesirable toxicity in human use (see for example, Goodman and Gilman, The Pharamcoloqical Basis of Therapeutics, Seventh Ed. (1985) Chapter 29 pages 674-715).
Wagner, et al., U.S. Pat. No. 4,029,812, and related U.S. Pat. Nos. 4,076,841 and 4,078,084 which issued from divisional applications of the -812 application, all assigned to The Dow Chemical Company, disclose 2-(3,5-di-tert-butyl-4-hydroxyphenyl) thiocarboxylic acids, esters and simple amides which are hypolipidemics and are useful in reducing plasma lipid levels, especially cholesterol and triglyceride levels.
European Patent Application No. 86 101 300.1 discloses 5-lipoxygenase inhibiting compounds which are useful as anti-inflammatory and anti allergy agents and which are represented by the formula ##STR4## wherein R.sub.1 and R.sub.2 are the same or different members of the group consisting of halo, phenyl, substituted phenyl and a ##STR5## group wherein q, r and t are independently an integer of from 1 to 8 provided that q+r+t is equal to or less than 10; Y is thio, sulfinyl or sulfonyl; Alk is straight or branched chain lower alkylene, and R.sub.3 is a heterocyclic amine represented by the formula: ##STR6## wherein R.sup.4 is selected from the group consisting of hydrogen, lower alkyl, phenyl, substituted phenyl, benzyl, substituted benzyl, carboxyl or carboxylower alkyl; X is selected from the group consisting of N--R.sub.4, O and CH.sub.2 ; m is 2 or 3; n is 2 or 3 when X is O or N--R.sub.4 and n is 1 to 3 when X is CH.sub.2 ; p is 0 to 2; and the pharmaceutically acceptable salts thereof.
USPTO Backgrounds
USPTO Backgrounds