MXPA96002640A - Use of derivatives of the 2-hydroxy-5-fenilazobenzoico acid as chemiopreventive and chemotherapeutic agents against cancer of co - Google Patents
Use of derivatives of the 2-hydroxy-5-fenilazobenzoico acid as chemiopreventive and chemotherapeutic agents against cancer of coInfo
- Publication number
- MXPA96002640A MXPA96002640A MXPA/A/1996/002640A MX9602640A MXPA96002640A MX PA96002640 A MXPA96002640 A MX PA96002640A MX 9602640 A MX9602640 A MX 9602640A MX PA96002640 A MXPA96002640 A MX PA96002640A
- Authority
- MX
- Mexico
- Prior art keywords
- hydroxy
- active metabolite
- asa
- oxidation product
- metabolite
- Prior art date
Links
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Abstract
The present invention relates to a process for depositing a silica coating on a heated glass substrate, comprising the following steps: a) providing the heated glass substrate, which has a surface on which the coating will be deposited; pre-mix a silane, a radical scrubber gas, oxygen and an inert carrier gas to form a precursor mixture, direct the precursor mixture to and along the surface to be covered in a laminar flow, and react the mixture on or near the surface to form the silica coating, the radical scavenger is present in such an amount that the index of the radical silane scavenger is between 3 to 1 and 17 to 1, and c) to cool the coated glass substrate at room temperature.
Description
USE OF ACID DERIVATIVES 2-HIDR0XI-5-FENILAZ0BENZ0IC0
1 AS CHEMICAL PREVENTIVE AND CHEMOTHERAPEUTIC AGENTS
OF COLON CANCER
DESCRIPTION OF THE INVENTION
Field of the Invention
The present invention relates to the chemo- prevention and chemotherapy of colon cancer. 10
Background of the Invention
Currently colon cancer represents 11% of all deaths due to malignancy, annually in the United States. With an incidence of 62 per 100,000 and a prevalence of 300 per 100,000, the disease is currently the third leading cause of death
* in men, and the fourth leading cause of deaths in 2Q women. Colon cancer has a five-year survival rate, particularly poor, of less than 50%, due to the late stage in which the diagnosis is generally made. The currently favored treatment, surgery combined with chemotherapy,
has failed to increase this proportion of survivors- REF: 22748 cia. What is needed is a safe and effective preventive therapy which could be initiated early in populations of patients known to be at increased risk of developing colon cancer.
Eicosanoids and Differentiated Functions of Gastrointestinal Cells. Eicosanoids are significant regulators of the growth, differentiation and function of gastrointestinal epithelial cells. It is known that the eicosanoid products of the pr ostaglandin series induce mucus secretion (Beckerl and Kauffman (1981) Gastroenterology 80: 770-776) and the secretion of electrolytes and fluid (Miller (1983) Am. J. Physiol 245: G601-G623). These also induce
active transport (Bukhave and Rask-Madsen (1980) Gastroenterology 7_8: 32-27) and increase the replication capacity of the epithelium (Konturek et al. (1981)
* Gastroenterology 8CJ: 1196-1201). These responses result in the maintenance of a barrier system
protective, differentiated, tightly bound epithelial cells, whose apical surface is covered by a dense gluco-conjugated chemical buffer. In the stomach and upper duodenum such a barrier protects against the acidic and proteolytic environment developed "for
digestion, while in the colon it protects against 1 the invasion of bacteria and toxins. It is therefore not surprising that synthetic, exogenous prostaglandins. are actively cytoprotective (Whittle and Vane (1987) In: Johnson (ed.) PHYSIOLOGY OF THE GASTROINTESTINAL
TRACT, Vol. 1, 2nd ed., New York: Raven Press, pp. 143- 1980) and have found therapeutic utility as secondary anti-ulcer treatments. The gastrointestinal system ("GI") has therefore evolved to actively produce and depend on a different specific complement of eicosanoid products present in the local environment. Since all eicosanoids are derived from a common precursor arachidonic acid, which is itself released from the phospholipids of the membrane, the gastrointestinal mucosal cells have a relatively high basal level of arachidonate productivity, initiated by the enzyme phospholipase A "(PLA"). The gastrointestinal system is also a primary defense mechanism against environmental bacteria, antigens and toxins, and should therefore
also possess the ability to mount an aggressive and rapid inflammatory response. This response also depends on the eicosanoid products of the prostaglandin (PG) series as well as the chemotactic leukotriene (LTs) series and results in the influx of
neutrophils, macrophages and immune cells carried by the blood, in response to the activation agents. Each of these invasive cells also carries with it an ability to metabolize its own phospholipids, as well as mucosal and luminal phospholipids, by releasing inflammatory (secreted) PLA to amplify the release of arachidonic acid, which is then metabolized in PGs and LTs. Although the infiltration of inflammatory cells confines and destroys the offending stimulus, the degree of damage due to the release products of inflammatory cells is significant. Neutrophils and macrophages release superoxide (0") (Kitahora et al. (1988) Dig. Dis. Sci. 33_: 951-955) as well as hydrogen peroxide (H 0) (Tauber and Babior (1985) Free Radie. Biol. Med.
1 ^: 265-307), and proteases (Ohlsson et al. (1977) -Hoppe Seylers Z. Physiol. Chem. 358: 361-366). Where the resulting infiltration is extensive, significant stripping of the epithelial layer occurs, with a subsequent compromise of the barrier function. The resolution of the inflammatory response is then required to recover the optimal, final epithelial network coverage.
Chronic Gastrointestinal Inflammation and Induction of Gastrointestinal Cancer. It is now well documented that chronic gastrointestinal inflammatory diseases such as ulcerative colitis (Lennard-Jones et al. (1977) Gastroenterology 73: 1280-1285), Crohn's disease (Farmer et al. (1971) Cancer 2 S_: 289-295 ), and chronic atrophic gastritis (Sipponen et al. (1983) Cancer 52: 1062-1067) are associated with an increased risk of subsequent gastrointestinal cancer. Although the mechanisms are not yet proven, during the acute multiple inflammatory episodes three important intersection pathways occur, which could lead to subsequent transformation, increased proliferation and malignant invasion. As discussed below, there are: (1) increased loading of colonic free radicals and carcinogenic substances, (2) altered regulation of trophic eicosanoids, and (3) induction of genetic products that mediate cell invasion.
Altered carcinogenic load due to inflammatory episodes. The colon can only be exposed to a clearly high l load of genotoxic carcinogens and tumor promoters, resulting from the metabolism of dietary compounds and endogenous secretions such as bile acids by colonic bacteria. A relationship between fecal carcinogens and the induction of colon cancer is supported by the findings of increased mutagens in the evacuations of high-risk individuals versus those of low-risk populations (Reddy et al. (1980) Mut. Res. 7J2: 511 -515). This correlation is also consistent with the repeated findings that show a negative association between dietary fiber intake and the incidence of colon cancer (Armstrong and Dolí (1975) Int. J. Cancer 1_5_: 617-623). It is postulated that the protective effect of
* 10 fiber occurs through an increase in the volume of the evacuation, which results in a dilution of the carcinogens of the excrement and decreased transmission time, which leads to more rapid elimination of carcinogens. These results raise the possibility
that if a reduction in the concentration of the carcinogen load in the evacuation can lead to a decreased cancer risk, then an increase in
# the load of carcinogens can lead to an increased risk. Such an increase in carcinogens
colonic could be derived from successive inflammatory events. A particularly relevant example is the production of inflammatory neutrophils from carcinogenic nitrosamines, via the L-25-dependent formation of arginine nitrogen oxides, such as nitric oxide (Grisham (1993) Gastroenterology 104: A243). Other oxidative products released by inflammatory cells include superoxide, as well as hydrogen peroxide, which in the presence of certain transition metals such as iron (Fe) can generate the hydroxyl radical (OH :) highly reative and cytotoxic (Grisham ( 1990) Biochem Pharmacol 3_9: 2060-2063). In addition to the increased carcinogen and free radical load, elaborated by the influx of inflammatory cells, it is also known that the arachidonic acid cascade is capable of producing mutagenic metabolites. A metabolite of prostaglandin H2 (PGH2), malondialdehyde (MDA) is a mutagen of direct action in vitro (Mukai and Goldstein (1976) Science 191: 868-869) and a carcinogen in animals ( and 'Marnett (1983) Carcinogenesis _ : 331-333) and can be enzymatically produced by thromboxane synthetase with high cell yields, with an active cyclooxygenase pathway. It has been shown that MDA produces structure change mutations, similar to those associated with the human colon p53 gene (Marnett et al. (1985) Mutat, Res. 129: 36-46). PGH-synthase itself is a potent peroxidase and has also been shown to catalyze the activation of a wide range of polycyclic hydrocarbons to mutagens (Marnett (1981) Life Sci. 29: 531-546).
These findings suggest that chronic and aberrant activation (promoted by inflammatory cells) of the arachidonic acid cascade in the gastrointestinal tract is a pathway that can lead to an increased burden of carcinogens, with the potential induction of DNA mutagenesis during the maximum DNA synthesis times. Increased cell proliferation, which follows the epithelial stripping induced by the invasion of inflammatory cells, could lead to an increased number of cells susceptible to the action of such carcinogens. Alternatively increased proliferation could serve to amplify mutations (through clonal expansion) previously induced by carcinogens.
The altered regulation of eicosanoids may promote proliferation due to inflammatory episodes. An additional mechanism that links gastrointestinal inflammation and the progression of gastro-intestinal cancers could be an interruption in the normal regulation of eicosanoids. As discussed above, the normal differentiated functions of the gastrointestinal mucosal epithelium are intimately linked to the wide range of biological activities affected by endogenous eicosa noids. Since these agents act locally #, and generally have short half-lives due to active metabolic inactivation, periods of acute inflammatory events will dramatically alter the normal regulation of eicosanoid homeostasis. With the invasion of neutrophils and macrophages towards an inflammatory site, these normal dynamics are dramatically altered. First, the inflammatory cells bring with them a wide range of additional agonists such as cytokines, proteases, and growth factors (Adams and Hamilton (1984) Ann. Rev.
"10 Immunol.2: 283-318, Ohlsson et al. (1977) Phisiol. Chem. 358: 361-366, Nathan and Cohn (1980) In: Kelly et al. (Eds.), Textbook of R'heumatology, New York : WB Saunders, pp. 186-215), which by
themselves chronically activate the cellular "PLA (cPLA2) to release arachidonic acid. Second, the inflammatory cells are a rich source of additional forms of PLA, "known as secretory or sPLA" (Seilhamer
• et al (1989) J. Biol. Chem. 264: 5335-5338),
whose activities in gastrointestinal inflammatory disease have recently been documented (Minami et al. (1992) Gut 33: 914-921). Contrary to cPLA, "sPLA" is released from inflammatory cells (Wright et al.
(1990) J. Biol. Chem. 265: 6675-6681). of platelets (Hayakawa et al. (1988) J. Biochem. 10: 767-772), of chondrocytes (Lyons-Goirdano et al.
(1989) Biochem. Biopys. Res. Commun. 164: 488-495) and smooth muscle cells (Nakano et al.
(1990) FEBS Lett. 261,171-174) by cytokines (Pfeilscifter et al. (1989) Biophys. Res. Commun. 15: 385-394), and, in particular, by endotoxin (Oka and Arita (1991) J. Biol. Chem. 266: 9956-9960). In addition, because the extracellular medium contains maximum calcium concentrations, sPLA_ is deregulated once released. When released, you therefore actively hydrolyze arachidonic acid and other fatty acids from the sn-2 position of the phospholipids found in cell and bacterial membranes, as well as those
of the sources of diet and lipoproteins. The resulting lysophospholipid resulting from the removal of the sn-2 fatty acid from many such phospholipids is potentially lysogenic for surrounding cells (Okada and Cyong (1975) Jpn. J. Exp. Med. 45: 533-534).
In this way, this reaction can also lead to the lysis of the epithelial cells and to the stripping in the infiltrated area, requiring the last increased proliferation to maintain the barrier function.
2 Inflammatory response and activation of # genes, which direct cellular invasion. The inflammatory response not only interrupts the normal regulation of eicosanoids, but also leads to the activation of genetic products required for cell invasion. One such product, the urokinase plasminogen activator receptor (uPAR), is normally expressed by intestinal epithelial cells. Its anchoring to the cell surface can be an important determinant of migration # and normal desquamation of cryptic cells, via cell surface proteolysis (Kristensen et al. (1991) J. Cell. Biol. 115: 1763-1771) . In inflammatory cells, the expression of the uPAR gene is induced by the activators of protein kinase C, by tumor promoters such as the
forbol TPA (Lund et al. (1991) J. Biol. Chem. 266: 5177-5181), and for various cytokines (Lund et al. (1991) EMBO J. ITJ: 3399-3401) which induce an invasive phenotype, required for tissue infiltration (Stoppelli et al. (1985) Nati. Acad.
Sci. USA 82_: 4939-4943). It is therefore not surprising that high levels of uPAR expression have also been detected in several tumor cell lines with metastatic potential, including cells derived from colon cancer (Pyke et al. (1991) Am. J.
Pathol. 138: 1059-1067). Of particular interest are f. co-culture experiments, which show that the invasive potential was more highly correlated with the expression of uPAR than its ligand plasminogen activator (Ossowski et al. (1991) J. Cell. Biol. 115: 1107-1112). Thus, multiple cycles of inflammatory responses may also contribute to the overexpression of uPAR in cells of the colonic mucosa, resulting in the acquisition of an 'invasive phenotype in a previously benign tumor. The cells of the gastrointestinal mucosa can
therefore only be sensitive to chronic inflammatory episodes, due to three intersecting pathways: (1) the epithelial cells are placed in an environment with a high carcinogenic load, which can also increase during episodes
inflammatories; (2) the products of eicosanoid cascades, endogenous and infiltrated, are trophic agents; and (3) its own differentiated response to inflammatory agents includes the expression of gene products required for the acquisition of an invasive phenotype.
Together these three pathways could lead to the transformation event and the resulting induction, progression and tumor invasion. Therefore, agents that block certain arms of the eicosanoid cascade are
useful in the chemoprevention of colon cancer.
#, Aberrant Cryptic Polyps and Foci as Precursors of Colon Cancer. It is now widely held that adenomatous polyps are precursors of colorectal cancer and their appearance, size and multiplicity are factors that predict the relative risk of developing colon cancer (see Lotfi et al. (1986) Mayo Clinic Proc. 61: 337-343). ). While adenomatous polyps are precursor lesions of colon cancer, it is now also accepted
* 10 that certain early pathological lesions, called aberrant cryptic foci, are precursor lesions for adenomatous polyps. Aberrant cryptic foci (ACF) are dentifiable in the normal-appearing human colon mucosa, and have been shown to be present
in a greater number and size in specimens from patients with sporadic colon cancer or in general inherited familial adenomatous polyposis (Ronucucci et al.
# collaborators (1991) Human Pathol. 22 (3): 287-29; Pretlow et al. (1991) Cancer Res. 51: 1564-1567). 20 NSAIDs and Chemoprevention of Colon Cancer. There is evidence that various non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing the number of animals that have tumors
and tumor incidence per animal in rat models of ^^ T 1 colon carcinogenesis. (Narisawa et al. (1981) Cancer Res. 41 :: 1954-1957), (Pollard et al. (1983) Cancer Lett. 21_: 57-61) (Moorghen et al. (1988) J. Pathol. 1956: 341-347 ) (Reddy et al. (1993) Gastroenterology 10: A443) where up to a 70% reduction in tumor incidence has been noted at doses of 80% of the maximum tolerated dose. In a study of colon carcinogenesis induced by dimethylhydrazine, it was observed that sulindac reduces tumor incidence only when it is present during administration
of the carcinogen, but not if it is administered 17 weeks after the carcinogen (Moorghen et al. (1988) J. Pathol. 156: 341-347). In several retrospective studies, the intake
of aspirin has been evaluated as a chemopreventive therapy in the consequent incidence of colon cancer. The results of these studies have ranged from halving (Kune et al. (1988) Cancer Res. 4_8: 4399-4404) the risk of developing
colon cancer up to an increased risk by 50% (Paganini-Hill et al. (1991) J. Nati. Cancer Inst. 83_: 1182-1183). It should be noted, however, that any human study that uses aspirin and other NSAIDs, especially retrospective studies, _. they could be 2 defective or unreliable because of the induced frequency of gastrointestinal bleeding, which may allow earlier detection of the polyp or tumor in the NSAID group, through occult blood screening and sigmoidoscopy. Although retrospective studies with aspirin have provided erroneous results, the initial results for certain NSAIDs found in animal studies, summarized above, have been replicated in prospective human trials. The NSAID, sulindac,
# has shown in a double-blind crossover study,
placebo-controlled, randomized, which causes regression of polyps in nine patients with familial polyposis in less than 4 months (Labayle et al. (1991) Gastroenterology 101: 635-639). In addition, the
polyps growth resumed after the withdrawal of sulindac. This finding is significant because a 'similar study using indomethacin did not find
# influence on the regression of polyps (Klein et al. (1987 Cancer 60 ^: 2863-2868).
Since two NSAIDs derive their anti-inflammatory activity from the inhibition of cyclooxygenase, sulindac is a prodrug that is converted to its active metabolite, sulindac sulphide, by colon bacteria (Shen and Winter (1975) Adv. Drug. REs. 21: 89-245). In
In contrast, indomethacin is ingested in its active form, where it is absorbed mainly from the upper intestinal tract 1 for the systemic distribution (Hucker et al. (1966), J. Pharmacol. Exp. Ther. 153: 237-249). It is therefore likely that the concentrations of active metabolite distributed by sulindac to the colon are significantly higher than from indomethacin. This result suggests that a significant portion of the observed chemopreventive effect of NSAIDs is derived from the local action of the
^^ drug at the mucosal-lumen interface. 10 Although this evidence of NSAID-induced inhibition of the incidence of colon tumor in animal models suggests a mechanism of inhibition via the cellular cyclooxygenase tumor, confirmation of such a mechanism is needed. It has been shown that tumor tissue excised from animals treated with NSAIDs secretes dramatically reduced levels of PGE ", which is consistent with this hypothesis (Reddy et al. (1992) Carcinogeneis L3: 1019-1023). However, the majority of colonic 2Q tumors are heterogeneous with respect to their resident cell types, and several reports have documented that epithelial cell lines generated from colorectal adenocarcinomas are not high producers of PGE "or other prostanoids ( Hubbard et al. 25 (1988) Cancer Res. 48: 4770-4775). A report on the # production of eicosanoids from fractionated cells from human colon tissue, however, showed that tumor epithelial cells produced PGE levels similar to non-involved tissue, whereas mononuclear cells derived from the tumor showed synthesis of eicosanoid significantly higher than its normal counterparts (Maxwell et al. (1990) Digestion 47_: 160-166). Therefore, target cells sensitive to inhibition by NSAIDs can not be tumor epithelial cells, but could be some other resident that produces high levels of PG for which the epithelial cells are responding.
Profile of Preferred Chemopreventive Therapy.
All NSAIDs have significant side effects profiles. NSAIDs are not tissue specific in their inhibition of cyclooxygenase products, and in the renal and gastrointestinal systems they are particularly sensitive. NSAIDs reduce renal perfusion resulting in nephrotoxicity (Clive and Stoff) N. Engl. J. Med. 310: 563-572), and because prostaglandins are necessary for the normal differentiated functions of the gastrointestinal epithelium, ulceration
Gastric-induced NSAID is a significant contributor to the morbidity and mortality associated with this class of drugs (Langman (1989) Gastroenterology 104: 1832-1847). In the lower bowel, it has been reported that chronic NSAID therapy results in colitis ranging from proctitis to pancolitis (Tanner and Raghunat (1988) Digestion 4 ^: 116-120). In a retrospective study, it was estimated that NSAID ingestion was found in 25% of patients presenting perforation and bleeding of the large and small intestine (Langman et al. Q (1985) Br. Med. J. 290: 347-349). Finally, in patients with chronic inflammatory bowel diseases, those who are already at high risk of developing colorectal cancer, therapy with NSAIDs that do not contain 5-ASA as well as with aspirin is contraindicated due to the exacerbation of the condition. of the existing disease (Rampton and Sladen (1981) Prostaglandins 21: 417-425). The ideal drug for the chemoprevention of colon cancer is, therefore, one with the following profile: 1) Colon specific - This must be 0 a prodrug without elaborate activity in the upper gastrointestinal tract, but converted to the active form upon reaching the colon (similar to sulindac); 2) Limited absorption - Absorption of the parent compound and the metabolites must be minimal, especially once converted to its active form;
3) Lack of systemic activity - Once absorbed, the metabolic inactivation must convert the drug to an inactive form, limiting the systemic effects on the renal and gastrointestinal systems; 4) Antioxidant properties - The specific antioxidant activity of the colon could additionally serve to distribute the carcinogenic charge; and 5) Anti-inflammatory mechanism similar to NSAID - The active metabolite must inhibit the pathways of eicosanoids induced by inflation, however, the inhibition of eicosanoids without compromise of the basal maintenance pathways, should be preferred. To summarize, it has been shown that certain NSAIDs, and inhibit the incidence of colon tumor in animal models induced with carcinogens, and inhibit the growth of polyps in humans. Although the mechanism for tumor inhibition by NSAIDS is not proven, these drugs can modulate gastrointestinal production of eicosanoids and their metabolism. Unfortunately, NSAIDs also have a disturbing and serious gastrointestinal side effects profile, which can exclude their chronic use. Therefore, it should be highly desirable to identify the 25 NSAIDs that are effective as chemopreventive agents, but which lack these side effects. Chan, in US Pat. No. 4,412,992, describes the preparation of 2-hydroxy-5-f-enylazobenzoic acid derivatives and their use in the treatment of colitis.
ulcerative.
Description of the invention
In accordance with one embodiment of the present invention, a method of treating an individual suffering is provided. of colon cancer, or at risk of developing colon cancer, comprising administering to the human an effective amount of a pharmaceutical composition comprising a 5-hydroxy-5-phenylazobenzoic acid derivative of the general formula:
0
wherein X is a group -S0"- or -CO- and R is either a phenyl or carboxymethylphenyl radical, or is a radical
of the formula - (CH2 ^ n ~ Y 'in which Y is a SruP ° hydroxyl, an amino group, a monoalkyl- or dialkyl-amino group, - -
the alkyl portions of which contain up to 6 carbon atoms, or a carboxylic or sulfonic acid group, and n is an integer from 1 to 6, and in which one or more of the hydrogen atoms in the alkylene radicals can be replaced by amino groups, by mono-alkyl- or dialkyl-ano groups, the alkyl portions of which contain up to 6 carbon atoms, or alkyl radicals, and in which the radical (CH ") -Y is attached either directly to the nitrogen atom or by means of a benzene ring, with the proviso that R-NH-X- is different from a radical -C0-NH-CH2-C00H; or an active ester or metabolite or an oxidation product of an active metabolite thereof, or a pharmacologically acceptable, non-toxic salt, of the 2-hydroxy-5-phenylazobenzoic acid derivative or an active ester or metabolite, or a product of oxidation of an active metabolite thereof. According to yet another embodiment of the present invention, the pharmaceutical composition of the method consists essentially of the 2-hydroxy-5-phenylazobenzoic acid derivatives or an ester or an active metabolite, or a product of oxidation of a metabolite. active itself, or a salt of the 2-hydroxy-5-phenylazobenzoic acid derivative or an ester or a metabolite thereof, in admixture with a solid or liquid pharmaceutical * diluent or carrier. In yet another embodiment of the present invention, the 2-hydroxy-5-phenylazobenzoic acid derivative is balsalazide. In a further embodiment of the present invention, the active metabolite is 5-ASA. In yet another embodiment of the present invention, the oxidation product of an active metabolite is an oxidation product of 5-ASA. # 10 In a further embodiment of the present invention, the oxidation product of 5-ASA is the genetic acid or the 5-nitro-salicylate. In a further embodiment of the present invention, the pharmaceutical composition is administered orally
to an individual suffering from or at risk of developing colon cancer, in a daily dosage range of 1 to 14 grams per 70 kg of body weight,
* per day, of the 2-hydroxy-5-phenylazobenzoic acid derivative or an ester or an active metabolite, or a product
Oxidation of an active metabolite thereof, or a salt of the 2-hydroxy-5-phenylazobenzoic acid derivative, or an ester or an active metabolite or an oxidation product of an active metabolite thereof. In still another embodiment of the present invention,
2 the pharmaceutical composition is administered rectally #, to an individual suffering from or at risk of developing colon cancer, in a daily dose in the range of 1 to 14 g per 70 kgs of body weight, per day, of the derivative of 2-hydroxy-5-phenylazobenzoic acid or an ester or an active metabolite, or an oxidation product of an active metabolite thereof, or a salt of the 2-hydroxy-5-phenylazobenzoic acid derivative, or an ester or an active metabolite , or an oxidation product of an active metabolite thereof. # 10 Brief Description of the Drawings
Figure 1 shows the chemical structure of a 2-hydroxy-5-phenylazobenzoic acid derivative in
where the generic name is balsalazide. The aminosalicylate moiety, 5-aminosalicylic acid (5-ASA) is linked to a carrier molecule 4-aminobenzoyl-beta-alanine
? M (4-ABA), through an azo link.
to Figure 2 shows the effects of 5-ASA on the proliferation of the HT-29 adenocarcinoma cell line, at doses of 0, 0.1, 1.0 and 10 mM. The cell numbers shown are the average of experiments in triplicate. 25 #, Figure 3 shows the effects of 5-ASA on the proliferation of the adenocarcinoma cell line
LS174T, at doses of 0, 0.1, 1.0 and 10 mM. The cell numbers shown are the average of experiments per triplicate.
Figure 4 shows an analysis of the number of aberrant colonic crypts, induced by the rat treatment groups, with the carcinogen, azoxymethane
# Q in the presence and absence of balsalazide, administered in drinking water.
Figure 5 shows the relative inhibitory responses produced by balsalazide and 5-ASA at 1 lower concentrations.
Figures 6A and 6B show the distribution of the aberrant crypt foci throughout the colon of the control animals and of the animals injected with AOM (20 mg / kg), 6 weeks after the second injection, respectively. The number of foci containing 1, 2, 3, 4 or 5 or more is displayed (bottom to top curves in each panel, respectively).
Figure 7 shows the inhibition of proliferation of LS174T cells by various concentrations of 5-ASA dissolved in media, 4 days before exposure to cells (black) or 5-ASA dissolved at 10 mM in media, immediately before exposure to cells (blan-co). Cells develop for an additional 4 days before quantification.
Figures 8A and 8B show the inhibition of colon cancer cell proliferation by measuring various concentrations of two oxidation products of 5-ASA, namely gentacyte and 5-nitro-salicylate, respectively.
Ways to Carry Out the Invention
The 2-hydroxy-5-phenylazobenzoic acid derivatives, particularly balsalazide and its active metabolites, have been found effective in the chemo-prevention of colon cancer. These 2-hydroxy-5-phenylazobenzoic acid derivatives have the following general formula:
R_NH- X wherein X is a group -S02"° -C0-; and R is either a phenyl or carboxymethylphenyl radical, or is a radical of the formula - (CH") -Y, in which Y is a group hydroxy-2-n-1, an amino group, a monoalkyl- or dialkyl-amino group, the alkyl portions of which contain up to 6 carbon atoms, or a carboxylic or sulfonic acid group, and n is an integer from 1 to 6, and in which one or more of the hydrogen atoms in the alkylene radicals can be replaced by amino groups, by mono-alkyl- or dialkyl-amino groups, the alkyl portions of the
Which contain up to 6 carbon atoms, or alkyl radicals, and in which the radical (CH ") -Y is attached either directly to the nitrogen atom or by means of a benzene ring, with the proviso that R- NH-X-15 is different from a radical -CO-NH-CH -COOH. As used herein, the term "2-hydroxy-5-phenylazobenzoic acid derivative" also encompasses
* the active esters or metabolites of the compound, or the non-toxic and pharmaceutically acceptable salts of the compound, or their esters or active metabolites. The term "active metabolite" refers to the products of metabolism of the 2-hydroxy-5-phenylazobenzoic acid derivatives in the human body, for example, by means of the action of the bacteria of the human body.
colon, which inhibits the proliferation of canee-pink colon cells. For example, as discussed below, 5-ASA is an active metabolite of balsalazide. The term "oxidation product" refers to products produced by exposure of the active metabolites of 2-hydroxy-5-phenylazobenzoic acid derivatives, for example, 5-ASA, to oxidation conditions such as with hypochlorite or peroxide. of hydrogen. Sodium balsalazide is a non-steroidal, anti-inflammatory specific colon aminosalicylate, which is useful in the treatment of active ulcerative colitis. Balsalazide as well as one of its main metabolites inhibits the growth of cells in human colon cancer culture, and balsalazide inhibits the formation of aberrant crypts in animals treated with carcinogen azoxymethane. Like other NSAIDs, balsalazide is effective in the chemoprevention of human colorectal cancer. However, balsalazide has three important safety advantages: (1) the distribution of the drug is specific to the colon; (2) no evidence of gastric or duodenal ulceration has been observed; (3) no evidence of nephrotoxicity has been reported among more than 500 patients treated to date, some as long as three years. Balsalazide therefore has an ideal combination of efficacy and safety for the chemoprevention of colon cancer.
Specific distribution of the colon. Balsalazide is a prodrug, the inactive form of which, like sulindac, is converted to an active anti-inflammatory drug by the action of colon bacteria. As shown in Figure 1, balsalazide binds the aminosalicylate, 5-aminosalicylic acid (5-ASA) to an inert carrier molecule, 4-aminobenzoyl-beta-alanine (4-ABA), through an azo bond. Bacterial azorreductase hydrolyzes this bond, releasing 5-ASA for local action.
Limited systemic absorption. Balsalazide, when taken orally, passes without cleavage and is virtually unabsorbed through the upper gastrointestinal tract. As little as 0.3% of the ingested dose of the prodrug is found in the plasma or in the urine, with 99% of the drug reaching the colon, intact. In the colon, the drug undergoes hydrolysis to form 5-ASA and 4-ABA, which interact with the mucosa of the colon and are converted to their N-acetylated forms. Most of the 5-ASA, which results from a single dose of balsalazide, is converted in a 96-hour period to N-acetyl-5-ASA (Nac5ASA) and excreted in the urine, while the 4-ABA and its N-acetylated metabolite are poorly absorbed. Since the N-acetylated metabolite of 5-ASA is inactive, the systemic activity of distributed 5-ASA is also reduced (Chan et al. (1993) Dig. Dis. Sci. 28: 609-615).
Antioxidant properties As previously discussed, a chemopreventive agent that possesses effective antioxidant properties can also contribute to a reduction in the carcinogenic burden of the colon, as well as to the reduction of damage induced by the release of free radicals that invade inflammatory cells. 5-ASA inhibits the formation of nitrosamine from the nitric oxide dependent on arginine (Grisham (1993) Gastroenterology 104: A243). In addition, balsalazide and intact 5-ASA are effective scavengers of free radicals against 0"- and OH :, balsalazide and 5-ASA, when incubated with rectal biopsies from patients with ulcerative colitis, reduce the production of oxygen metabolite reactive with the rectal mucosa, for more than 90%. Both agents are also more effective than the antioxidants taurine, ascorbate or N-acetyl-cysteine, when used at similar concentrations (Simmonds et al. (1992) Gastroentero log y 102: A696)
Anti-inflammatory activity of the colon without effects in the upper gastrointestinal tract. Balsalazide has anti-inflammatory activity in several animal models of colon inflammation, as well as in patients with active ulcerative colitis (Green et al. (1993) Gastroenterology 104: A709) and at rest (Gaiffer et al. (1992) Ailment. Pharmacol. 6 ^: 479-485). Importantly, the drug shows excellent gastrointestinal tolerance.
B alsalazide and 5-ASA inhibit the proliferation of colon cancer cells in vitro. 5-ASA, as well as balsalazide, show significant inhibitory growth activity against human colon cancer cells.
The oxidation products of 5-ASA inhibit the proliferation of colon cancer cells in vitro. The oxidation products of 5-ASA show surprisingly unexpected growth inhibitory activity against human colon cancer cells when compared to 5-ASA.
Methods of Chemoprevention and / or Chemotherapy contributed to Colon Cancer.
The 2-hydroxy-5-phenylazobenzoic acid derivatives of the present invention, particularly balsalazide and its metabolites, are, therefore, useful for chemoatherapy against colon cancer. These will preferably be administered to human individuals suffering from colon cancer, or at risk of developing colon cancer in the form of pharmaceutical compositions comprising the derivative or derivatives of 2-hydroxy-5-phenylazobenzoic acid. The pharmaceutical composition may also comprise one or more carriers, pharmaceutically acceptable, non-toxic excipients and / or diluents. Oral administration is preferred. Standard pharmaceutical formulation techniques are used, such as those described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, latest edition. The compositions may be in the form of tablets, capsules, powders, granules, pellets, in liquid or gel preparations. Tablets and capsules for oral administration may be in an appropriate form for presentation in unit dose, and may contain conventional excipients. Examples of these are: binding agents such as syrup, acacia, gelatin, sorbitol, tragacanth and polyvinylpyrrolidone; fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycerin; lubricants for the formation of tablets, such as magnesium stearate, silicon dioxide, talc, polyethylene glycol or silica; disintegrators, such as potato starch; or acceptable wetting agents, such as sodium lauryl sulfate. The tablets can be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle, before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol, syrup, methylcellulose, glucose syrup, gelatin, hydrogenated edible fats, emulsifying agents, for example, lecithin, sorbitan monooleate or acacia; non-aqueous vehicles (including edible oils), for example, almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives such as methyl or propyl p-hydroxybenzoate, or sorbic acid, and, if desired, conventional flavoring or coloring agents. The percentage of active material in the pharmaceutical compositions of the present invention can be varied, it being necessary that it should constitute a proportion such that an appropriate dose will be obtained for the desired therapeutic effect. In general, the preparations of the present invention should be administered orally or rectally to humans, to give 1 to 14 g of the active substance per day per 70 kg of weight
corporal. The following examples are offered by way of illustration and not by way of limitation.
EXAMPLES Example 1: Balsalazide and 5-ASA inhibit the proliferation of colon cancer cells in vitro The activity of balsalazide and its metabolite 5-ASA on the growth of human colon cancer cells was demonstrated in vitro using the HT-29 and LS174T lines of human adenoma cells. Cells were grown in Dulbecco's Modified Eagle medium, supplemented with 10% calf serum in an atmosphere of 5% C0"at 37 ° C. For the growth experiments * the cells were seeded in 24-well tissue culture plates (2 cmVpozo) at a density of 20,000 cells / well, and allowed to adhere for 12 hours. The growth medium was then changed and replaced with fresh medium containing the test drugs. The test drugs were dissolved in the tissue culture media at the desired concentration, and added to the individual wells. To determine the number of cells per well, the means
were removed and the cells were washed with phosphate buffered saline. The cells were then incubated 15 minutes with trypsin-EDTA solution until they were detached. The detached cells were then removed from the wells and counted using a Counter
Coulter (Model ZBI). As shown in Figures 2 and 3, HT-29 and KS174T lines of human cancer cells were inhibited in their growth by
• progressively higher concentrations of 5-ASA. At a dose of 10 mM 5-ASA the inhibition reached 82% and 85%,
respectively. Comparative studies were also carried out to test the effectiveness of balsalazide with its two metabolites, 5-ASA and 4-ABA, as well as acetylsalicylic acid (aspirin) on the proliferation
2 ^ of the cancer cells. As shown in Table # I, acetylsalicylic acid, which covalently inhibits cycloxygenase, was potently inhibitory in this assay, as was the mother drug balsalazide. However, 4-ABA, the carrier molecule of balsalazide, was inactive. The cell numbers shown in Table I are the average of triplicate culture wells.
TABLE I # 10 HT-29 LS174T
Condition Dosage N of cells% of cells Ns of cells% of cells on day 10 Control on day 10 Control
Control - 1315800 - 709750 - Ac-salicylic acid (10 pM) 14625 1. 11 8300 2. 24
* Balsalazide (10 mM) 47500 3.60 24925 3.51
5-ASA (10 mM) 512825 38.97 8675 1 .22 4-ABA (10 mM) 1316625 100.06 763700 108.30
Additional studies designed to examine the dose-response relationship of the inhibitory effect of
Growth, observed with balsalazide and 5-ASA, showed that both compounds produced similar results when examined using either HT-29 cells or LS174T cells. For the dose-response studies, a sensitive dye binding assay was adapted, which allows simultaneous testing of multiple agents and doses in 96-well plates. The cells were plated and allowed to adhere for 24 hours before the addition of the study drug. The cell densities were then determined 4
# 10 days later by fixing the wells and staining with Sulforrodamine B dye. The optical density of the stained cultures was then determined using a 96-well plate reader at 495 nm (Skehan et al. (1990) J. Nati. Cancer Inst. 82: 1107-1112).
As shown in Figure 5, balsalazide consistently produced a greater inhibitory response at doses lower than 5-ASA. Using HT-29 cells
* IC n values were 5.7 mM and 11.8 mM respectively, while using the LS174T cells
the respective IC Q values were 5.2 and 11.5 m. At the lowest concentrations of 5-ASA, tested (0.1-1.0 mM for LS174T and 0.1-4 mM for HT-29), a reproducible and statistically significant increase in the number of cells was observed.
20%, with both cell types. This is consistent with the results previously published by others, who observed an increase in protein synthesis induced by other NSAIDs at low concentrations, followed by an inhibition at higher concentrations (Hial et al. (1977) J. Pharm. Exp. Therap 202: 446-452).
Example 2: Influence of balsalazide and metabolites on the formation of aberrant crypts in the rat. ^ 10 Aberrant crypts were originally described in colonic mucosa induced by carcinogen, as crypts of "increased size, thicker epithelial lining and increased perripral areas"
(Bird et al. (1989) Cancer Sury. 8_: 189-200). NSAIDs are among the most potent inhibitors of aberrant crypt formation, induced by the carcinogen, azoxymethane (AOM), in the rat (Wargovich • et al. (1992) J. Cell. Biochem. 16G: 51-54). The ac¬
The antitumor activity of several of these agents has been confirmed in animal studies with AOM, in the long term. The aberrant crypt model is, therefore, an ideal in vivo assay for the efficacy of balsalazide and metabolites. 25 F. Inhibition of the Induction of Aberrant Crypts. The efficacy of balsalazide (BSZ) and its metabolites, 5-aminosalicylic acid (5-ASA) and 4-aminobenzoyl-beta-alanine (4-ABA) on the inhibition of aberrant crypt formation, was determined in a model of colon cancer, induced by azoxymethane (AOM) in the rat. Four groups of 5 male F344 rats were used. The animals were 6 to 8 weeks old at the beginning
^^ 10 of the dosage, with an initial weight interval between +/- 20% of the total average. The expected response for treatment with AOM from the published studies is the formation of 100 to 140 aberrant crypts per animal (Wargovich et al. (1992)
J. Cell. Biochem. 16G: 51-54). Using these response ratios and a chi square analysis with 95% confidence limits, the sample size of 5 animals per group allows the detection of statistically significant inhibition (at the p <0.05 level) by
the test drugs, when up to 50-75 aberrant crypts are observed per animal. The animals were acclimated for 10 days before being randomized into the test groups by body weight classes. The test drug was dissolved
in drinking water, at a concentration that gave the desired dose per animal, per day, based on. an average water consumption of 50 ml per day per animal. Two groups were left a week of drug treatment before the AOM injections. Carcinogenesis was induced by two subcutaneous injections of AOM at 20 mg / kg, given at the beginning of week 2 and week 3. The dosage of the test article was then continued until the end of week 5. The choice of level of Dosage for balsalazide is done by reviewing other preclinical studies for efficacy in colitis models. A dose of 200 mg / kg / day in a 500 g rat equals a dose of 14 g per day in a 70 kg human, approximately twice the therapeutic dose for the treatment of active ulcerative colitis, and above 4 times the dose for maintenance of remission. This dose level results in colonic concentrations of 5-ASA, 5-20 mM. The maximum tolerated dose of balsalazide in the rat is greater than 12,000 mg / kg / day. The body weights were recorded twice a week, and the water consumed by each animal cage was measured twice a week. The consumption is calculated as the average ml / animal / classroom. For the analysis of the aberrant crypts, the animals were sacrificed under euthanasia with C0"gl at the end of either three weeks or five weeks of dosing. The large intestine was removed in the cecum and anus, withdrawn and opened longitudinally. The tissue was released from the contents, rinsed with saline and fixed at 4 ° C for 2 hours in 2% paraformaldehyde and stained with 0.2% methylene blue for 3-5 minutes. After a saline rinse, the number of aberrant crypt foci was determined by counting under a microscope at an amplification
& 10 of 40-100X. The length of the colonic tissue was also meas. A representative sample of the more or less identified lesions was incrusted in glycol methacrylate at 4 ° C; Sections of 3-4 micras were stained from each of the foci, with hematoxylin, eosin and azur
(HEA) for histological evaluation. For the analysis of gastroduodenal erosion, the fundus, the antrum and the duodenum were removed and
# processed separately as described above. Gastric erosions were determined using the
index of length and severity of gastric erosion as described (Peskar et al. (1986) Prostaglandins 31: 283-287). The results are shown in Fig4, where the average number of aberrant crypts per
cm longitudinal of colonic tissue, is shown for animals examined either one or three weeks after two subcutaneous injections of azoxymethane. At both time points, the animals treated with balsalazide had a markedly reduced average number of aberrant crypts than the control animals. At week 1 there was an inhibition of 61.8%, and at week 5 there was an inhibition of 58.1% in the average number of aberrant crypts.
* 10 Inhibition of the Progression of Aberrant Crypts. The data shown in Fig4 were collected from the 7-8 cm distal colonic tissue. At these early time points, this area contained up to 80% of the total aberrant crypt foci.
It was therefore designed an additional study to examine a longer time point, to evaluate the distribution throughout the entire 25 cm of the
»Colon, and determine if treatment with the drug could be started after the second injection with
AOM. This last objective is of particular interest, because it is important to demonstrate that the chemopreventive agent is inhibiting the progression of the development of aberrant crypts after the event of initial transformation by the carcinogen. 25 In the second study, groups of 8 animals received two injections of azoxymethane within a week. The balsalazide treatment was then started with a group of 24 hours after the second injection. Six weeks later the animals were processed for the analysis of the aberrant crypts. The crypts were stained in situ by rectal instillation of a 0.2% solution of methylene blue for 15 minutes, under anesthesia. The animals were then bled, colonic tissue from the anus to the cecum was excised, cleaned and fixed for 2 hours in paraformaldehyde at 2%. The crypts were counted by observation at a magnification of 40x. In addition to collecting data on the number of outbreaks, data on the multiplicity of aberrant crypts per focus were also collected. These data are shown in Fig6. As is evident, even when the balsalazide was administered starting 24 hours after the second injection of AOM, a dramatic inhibition of aberrant crypt foci was observed, which was comparable to the previous experiment (approximately 60% of total inhibition) illustrated in Fig4. Previous studies by Pretlow et al. (Pretlow et al. (1992) Carcinogenesis 1_3: 1509-1512) have reported on the relationship between the multiplicity of aberrant crypts and tumor development final using the same model of carcinogenesis. In those studies, the number of aberrant crypt foci containing 4 or more aberrant crypts correlated strongly with tumor formation, suggesting that these major foci are those that most likely progress to tumors. The data from the previous experiment were analyzed to determine the effect of balsalazide on the multiplicity of aberrant crypts. These data are shown below in Table II, and reveal that balsalazide exerts a greater inhibition of the number of foci containing 4 or more aberrant crypts, than those with less than four. For the foci with 1 to 3 crypts the average inhibition was 57 to 61% (p <; 0.003, Fischer exact test) while the number of foci with 4 or more crypts was reduced by an average of 72-76% (p <0.001). When the results on the number of foci containing 4 or more crypts are compared with those that have 3 or less, the difference remains statistically significant at the level of p < 0.022, using Fischer's exact test.
TABLE II
Inhibition by Balsalazide of the Multiplicity of Aberrant Crypts. The numbers shown are the average number of foci of different sizes in each group of 8 animals, measured 6 weeks after the second injection with AOM
Multiplicity 1 5 to 8 Total
^ * 10 BSZ 10.3 19.1 15.3 8., 5 9.6 63.75 Control 24 48.8 37.3 30.5 40.6 181.75
% inhibition 57 ± 23% 61 ± 16% 59 ± 17% 72119% 76 ± 12% 65 ± 10%
Fischer 0.001 0.001 0.003 0.0001 0.0001 0.001
These results show that the foci containing the largest number of aberrant crypts, are
reduced almost twice than those foci containing 2 to 3 aberrant crypts. When interpreted in the context of the results of Pretlow and colleagues, it is likely that this inhibition will result in an inhibition of tumor formation, when
animals are examined at the last points of time.
Example 3: Influence of the oxidation products of 5-ASA on the proliferation of colon cancer in vitro.
Although the inhibition observed with balsalazide in the previous examples was identical between both cell types, the LS174T cells appeared consistently more sensitive to the actions of 5-ASA than the HT-29 cells. In addition, the inhibitory response of both cell types to 5-ASA varied between individual experiments from a maximum of 70% to a minimum of 10%. In the design of the experiments to determine the source of the variability, it was determined that the reserve solutions
of 5-ASA which were elaborated at least 3 days before the addition to the cells, consistently produced a greater inhibitory effect. This difference is demonstrated in Figure 7. In this experiment the growth of
LS174T cells exposed to freshly dissolved 10 mM 5-ASA, showed a growth response in 4 days, which was 82.7% of that shown by the control cells. In contrast, the growth of parallel cultures exposed to 10 mM 5-ASA, which had been dissolved in culture media 4 days before the start of the experiment, showed a growth response in 4 days that was only the 22.9% of that shown by the control crops. This significant difference suggested that 5-ASA was being converted to a more active metabolite while it was in the presence of certain components of the medium. One of the important activities associated with 5-ASA, is its antioxidant properties. Of course, it is thought that certain therapeutic benefits
* 10 in the treatment of intestinal inflammation are derived from its ability to purify free radicals, including 0"- released from inflammatory cells, and by this the oxidative damage reduced. This suggested that the observed changes in inhibitory activity,
associated with 5-ASA when pre-incubated in tissue culture media, could be consistent with an oxidation event. To test this possibility, 5-ASA was subjected to oxidation using sodium hypochlorite at various proportions, and then the activity was evaluated.
inhibitory of cell growth, subsequent. As shown in Table III below, increasing amounts of hypochlorite resulted in increased inhibitory activity of 5-ASA.
TABLE III
Increase in the Growth Inhibitory Activity of 5-ASA After Exposure to Hypochlorite
-ASA Hypochlorite "" - "Increase in (mM) of Na Inhibition of (mM) Growth (%)
or 0 10 0.01 2 10 0.05 4 10 0.1 8 10 0.2 26 10 0.3 42 10 0.4 48
* The basal inhibitory activity by non-oxidized 5-ASA was 45%. The background inhibitory activity by 0.4 mM NaOCl was less than 2%.
Previous studies by others have shown that oxidation conditions such as exposure to hypochlorite or hydrogen peroxide can give rise to several different metabolites of 5-ASA. Two such oxidation products, gentisic acid (Dull et al. (1987) Biochem Pharmacol 3_6_: 2467-2472) and 5-nitrosalicylate (Laffafian et al. (1991) Biochem. Pharmacol. 42: 1869-1874) have been elucidated. In view of the previous results, these two oxidation products of 5-ASA were tested for the inhibitory activity of the growth of colon cancer cells. As shown in Table IV below, using four different human colon cancer cell lines, both metabolites inhibited cell growth with the 5-nitro derivative, which appears to be more potent. The relative potencies of the balsalazide, its main metabolite, 5-ASA and two of the possible oxidation products of 5-ASA on the growth inhibition of each of the cell lines are shown in summarized form in Table IV below.
TABLE IV
IC, -n of Balsalazide and metabolites for the inhibition of the proliferation of human colon cancer cells. The concentrations are in mM
Line Balsalazida 5-ASA 5-ASAox Gentisato 5-NSA
Cell phone
LS174T 5.29 11.56 6.55 5.85 2.69
HT-29 5.71 11.89 5.91 5.05 1.63
LoVo 5.00 10.21 5.44 4.42 1.38
HRT-18 3.88 10.49 6.98 2.98 1.46
All publications and patent applications cited in this specification are incorporated by reference to the same degree as if each individual publication or patent application was speci fi cally and individually indicated as incorporated by reference. It will be apparent to one of skill in the art that changes and modifications may be made to the invention as now fully described, without departing from the spirit or scope of the appended claims.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.
Having described the invention as above, the content in the following is claimed as property:
fifteen
#
twenty
Claims (9)
1. A method for the treatment of an individual suffering from colon cancer or who is at risk of developing colon cancer, characterized in that the method comprises administering to the human an effective amount of a pharmaceutical composition comprising a derivative of 2-hydroxy acid -5-phenylazobenzoic acid of the general formula: - wherein X is a group -S0 ~ - or -CO- and R is either a phenyl or carboxymethylphenyl radical, or is a radical of the formula _ (CH ") -Y, in which Y is a group 2 n ° hydroxyl, an amino group, a monoalkyl- or dialkyl-amino group, the alkyl portions of which contain up to 6 carbon atoms, or a carboxylic or sulfonic acid group, and n is an integer from 1 to 6, and in which or more of the hydrogen atoms in the alkylene radicals can be replaced by amino groups, by monoalkyl- or dialkyl-amino groups, the alkyl portions of which contain up to 6 carbon atoms, or alkyl radicals, and in which the radical (CH ") -A and is attached either directly to the 2 n atom of nitrogen or by means of a benzene ring, with the proviso that R-NH-X is different from a radical -C0-NH-CH" -C00H; or an active ester or metabolite or an oxidation product of an active metabolite thereof, or a non-toxic pharmacologically acceptable salt of the 2-hydroxy-5-phenylazobenzoic acid derivative, or an ester or an active metabolite, or an oxidation product of an active metabolite thereof.
2. A method according to claim 1, characterized in that the pharmaceutical composition consists essentially of the 2-hydroxy-5-phenylazobenzoic acid derivative or an active ester or metabolite, or an oxidation product of an active metabolite thereof, or a salt thereof. 2-hydroxy-5-phenylazonbenzoic acid derivative or an ester or an active metabolite, or an oxidation product of an active metabolite thereof, in admixture with a solid or liquid pharmaceutical carrier or diluent.
3. A method of conformance with the > 1 claim 1, characterized in that the 2-hydroxy-5-phenylazobenzoic acid derivative is balsalazide.
4. A method according to claim 1, characterized in that the active metabolite is 5-ASA.
5. A method according to claim 1, characterized in that the product # 10 Oxidation of an active metabolite is an oxidation product of 5-ASA.
6. A method according to claim 5, characterized in that the oxidation product of 5-ASA is gentisic acid.
7. A method of compliance with * claim 5, characterized in that the oxidation product of 5-ASA is 5-nitro-salicylate.
8. A method according to claim 1, characterized in that the pharmaceutical composition is administered orally to an individual suffering from or at risk of developing cancer. 25 of colon, in a daily dose in the range of 1 # to 14 grams per 70 kilograms of body weight, per day, of the 2-hydroxy-5-phenylazobenzoic acid derivative or an ester or an active metabolite thereof, or a oxidation product of a metabolite thereof, or a salt of the 2-hydroxy-5-phenylazobenzoic acid derivative or an ester or an active metabolite, or an oxidation product of an active metabolite thereof.
9. A method according to claim 1, characterized in that the pharmaceutical composition is administered rectally to an individual suffering from or at risk of developing colon cancer, in a daily dose in the range of 1. 15 to 14 grams per 70 kilograms of body weight, per day, of the 2-hydroxy-5-phenylazobenzoic acid derivative or an ester or an active metabolite thereof, or an oxidation product of a metabolite thereof, or a salt thereof. 2-hydroxy-5-phenylazobenzoic acid derivative or an ester or an active metabolite, or an oxidation product of an active metabolite thereof. 25
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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US08178578 | 1994-01-07 |
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MXPA96002640A true MXPA96002640A (en) | 2000-06-05 |
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