JP2005527510A5

JP2005527510A5 -

Info

Publication number: JP2005527510A5
Application number: JP2003572598A
Authority: JP
Filing date: 2003-03-06
Publication date: 2006-04-20

Claims

Administering a phosphodiesterase inhibitor or adenylyl cyclase activator to a subject to modulate, treat and / or prevent cancer, malignancy, neoplasia, hyperplasia, hypertrophy, dysplasia and / or tumor angiogenesis A method of modulating, treating and / or preventing a subject's cancer, malignancy, neoplasia, hyperplasia, hypertrophy, dysplasia and / or tumor angiogenesis.

2. The method of claim 1, wherein the phosphodiesterase inhibitor or adenylyl cyclase activator is administered at a low dose.

Administer phosphodiesterase inhibitor or adenylyl cyclase activator at a concentration that delays and / or reduces the development of tolerability to phosphodiesterase inhibitor or adenylyl cyclase activator and / or unwanted side effects including headache, flushing and hypotension The method of claim 1.

2. The method of claim 1, wherein the phosphodiesterase inhibitor or adenylyl cyclase activator is administered alone or in combination with an anti-malignant disease treatment means .

A phosphodiesterase inhibitor or adenylyl cyclase activator ,
(1) Preferably, invasive cells exhibiting a malignant phenotype, progression, and reducing the growth and / or metastasis; indicates a malignant phenotype; that inhibit the survival and / or growth of cells exhibiting a malignant phenotype it reduces the progression and / or metastasis of the cells; it enhances regression of cells exhibiting a malignant phenotype; and / or, the phenotype of a tumor or malignant cells by promoting the killing of cells exhibiting a malignant phenotype inhibit the potential for metastasis;
(2) maintaining the malignant tumor dormant or quiet state at its primary and / or secondary site;
(3) enhance the effect of anti-malignant disease treatment means and / or prevent or reduce resistance to it; or
(4) in high risk subjects of developing cancer, and / or, in a subject in reducing the activity of nitric oxide target is exposed to known factors, inhibit or prevent tumor angiogenesis, And optionally the factor was reduced arginine concentration, exposure to nitric oxide synthase andagonist, exposure to nitric oxide scavenger, altered nitric oxide synthase expression, altered cofactor, glucose depletion, surgical 2. The treatment of claim 1 , including treatment, administration of anesthetics, administration of pharmacological agents that alter circulation, trauma injury, physical injury, blood loss, decreased blood volume, or bleeding, or combinations thereof Method.

The cell exhibiting malignant disease is selected from malignant cells, invasive cells, cells and tissues that promote malignant processes, and combinations thereof, optionally wherein the malignant cell phenotype is an anti-malignant disease therapeutic means 2. The method of claim 1, wherein the method is modulated, treated or prevented by improving the response to.

2. The method of claim 1, wherein cancer is diagnosed or monitored by measuring a tumor selectable marker present in the subject .

8. The method of claim 7, wherein the phosphodiesterase inhibitor or adenylyl cyclase activator decreases or delays the increase in tumor marker concentration.

Cancer or other malignant disease, neoplasm, hyperplasia, hypertrophy, dysplasia and / or tumor angiogenesis is gastric cancer, gastrointestinal cancer, testicular cancer, prostate cancer, prostate adenocarcinoma, breast cancer, metastatic melanoma, lung cancer, The method of claim 1, comprising benign prostatic hyperplasia, or premature pregnancy, or a combination thereof.

Phosphodiesterase inhibitor, or adenylyl cyclase activator dose of at least 3 to 10,000 fold lower than the dose of the phosphodiesterase inhibitor or adenylyl cyclase activator leads to vasodilation, preferably 100 to 10,000 times lower value, claim The method according to 1.

The phosphodiesterase inhibitor is a non-specific phosphodiesterase inhibitor, dual selective phosphodiesterase inhibitor, phosphodiesterase type I, type II, type III, type IV, type V, type VII, type VIII, type IX, type X or type XI or The method according to claim 1, which is a combination thereof.

12. The method of claim 11 , wherein the phosphodiesterase inhibitor is a phosphodiesterase type I, type II, type III, type IV, type V inhibitor or a non-specific phosphodiesterase inhibitor.

12. The method of claim 11 , wherein the phosphodiesterase inhibitor is a PDE type V inhibitor, for example: Cialis, vardenafil, tanadafil, zaprinast, MBCQ, MY-5445, dipyridamole, furoyl and benzofuroylpyrroloquinolone, 2- (2 -Methylpyridin-4-yl) methyl-4- (3,4,5-trimethoxyphenyl) -8- (pyrimidin-2-yl) methoxy-1,2-dihydro-1-oxo-2,7-naphthyridine -3-Carboxylic acid methyl ester hydrochloride (T-0156), T-1032 (methyl 2- (4-aminophenyl) -1,2-dihydro-1-oxo-7- (2-pyridylmethoxy) -4- (3,4,5-trimethoxy-phenyl) -3-isoquinolinecarboxylate sulfate) or sildenafil.

12. The method of claim 11 , wherein the phosphodiesterase inhibitor is, for example, a PDE type IV inhibitor as follows: Roflumilast, Ariflo (SB207499), RP73401, CDP840, Rolipram, Mesopram, Denbufilin, EMD95832 / 3, Siromilast, RO-20-1724 Or LAS31025.

Is a non-specific phosphodiesterase inhibitors such as phosphodiesterase inhibitors, for example, the following, according to claim 11 methods: theobromine, dyphylline, IBMX, theophylline, aminophylline, pentoxifylline, papaverine, caffeine or other methylxanthines.

12. The method of claim 11 , wherein the phosphodiesterase is a PDE type II inhibitor such as EHNA.

12. The method of claim 11 , wherein the phosphodiesterase inhibitor is a PDE type III inhibitor such as olprinone.

Phosphodiesterase inhibitor, is a dual-selective phosphodiesterase inhibitors such as zardaverine method of claim 11.

Phosphodiesterase inhibitors are phosphodiesterase inhibitors that can increase both cAMP and cGMP concentrations, such as satigrel (E5510, 4-cyano-5,5-bis (4-methoxyphenyl) -4-pentanoic acid) The method of claim 1 .

The method of claim 1 , wherein the adenylyl cyclase activator is selected from: forskolin, N6, O ₂ '-dibutyryl-cAMP, 8-chloro-cAMP and adenosine 3', 5'-cyclic monophosphorothioate Derivatives of forskolin, including Rp-diastereomers, and related analogs such as Rp-8-bromo-adenosine 3 ′, 5′-cyclic monophosphorothioate, and colforsin dalopate hydrochloride.

Use of an adenylyl cyclase activator in the manufacture of a pharmaceutical agent for modulating, treating and / or preventing cancer, malignancy, neoplasia, hyperplasia, hypertrophy, dysplasia and / or tumor angiogenesis.

Use of a phosphodiesterase inhibitor in the manufacture of a medicament for modulating, treating and / or preventing cancer, malignancy, neoplasia, hyperplasia, hypertrophy, dysplasia and / or tumor angiogenesis.