Method of treating colonic adenomas
AssigneesMerck & Co., Inc., Merck Frosst Canada, Inc.
InventorsStacia Kargman, Thomas J. Simon, Jilly Evans
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Abstract
This invention is directed to a method of retarding or preventing the transformation of a colonic adenoma to a colonic adenocarcinoma comprising the administration to a patient with FAP or a patient with one or more of said adenomas a non-toxic therapeutically effective amount of NSAID, said amount effective to inhibit the PGHS-2 in said adenoma. The preferred method comprises the administration of a specific PGHS-2 inhibiting agent as defined herein.
Claims19
A method of treating colonic adenomas in a patient in need thereof comprising administering to said patient a non-toxic therapeutically effective amount of an NSAID, with the proviso that said NSAID is not aspirin, ibuprofen, indomethacin, sulindac, dolobid, diclofenac, naproxen, piroxicam, etodolac, ketoprofen, flurbiprofen, meloxicam, flosulide or nabumetone,
- wherein said NSAID is a potent inhibitor of PGHS-2 and wherein said NSAID possesses a selectivity for inhibiting PGHS-2 over PGHS-1 of at least 100 fold as measured by the ratio of the IC50 for the inhibition of PGHS-2 to the IC50 for the inhibition of PGHS-1 in a whole cell or microsomal assay, said assay conducted by measuring the amount of prostaglandin E2 synthesized in the presence of arachidonic acid, PGHS-2 or PGHS-1 enzyme and said NSAID, and wherein said assay comprises the steps of:
- (1) incubating said NSAID with the cell or microsome expressing PGHS-2 or PGHS-1 enzyme for about 10 to 20 minutes prior to the addition of arachidonic acid, and
- (2) conducting said assay with arachidonic acid at a concentration of about 10 μM.
A method of treating colonic adenomas in a patient in need thereof comprising administering to said patient a non-toxic therapeutically effective amount of an NSAID, with the proviso that said NSAID is not aspirin, ibuprofen, indomethacin, sulindac, dolobid, diclofenac, naproxen, piroxicam, etodolac, ketoprofen, flurbiprofen, meloxicam, flosulide or nabumetone,
- wherein said NSAID is a potent inhibitor of PGHS-2 and wherein said NSAID possesses a selectivity for inhibiting PGHS-2 over PGHS-1 of at least 100 fold as measured by the ratio of IC50 for the inhibition of PGHS-2 to the IC50 for the inhibition of PGHS-1 in a microsomal assay, said assay conducted by measuring the amount of prostaglandin E2 synthesized in the presence of arachidonic acid, PGHS-2 or PGHS-1 enzyme and said NSAID, and wherein said assay comprises the steps of:
- (1) incubating said NSAID with the microsome expressing PGHS-2 or PGHS-1 enzyme for about 10 to 20 minutes prior to the addition of arachidonic acid, and
- (2) conducting said assay with arachidonic acid at a concentration of about 10 μM,
- wherein said NSAID possesses a potency for the inhibition of PGHS-2 of about 1 μM or less as measured by the IC50 for the inhibition of PGHS-2 in the microsomal assay, and
- wherein the microsomal assay is the CHAPS-solubilized recombinant PGHS-1 or PGHS-2 expressing insect cell membrane assay.
A method of retarding or preventing the transformation of a colonic adenoma to a colonic adenocarcinoma in a patient in need thereof comprising administering to said patient a non-toxic therapeutically effective amount of an NSAID, with the proviso that said NSAID is not aspirin, ibuprofen, indomethacin, sulindac, dolobid, diclofenac, naproxen, piroxicam, etodolac, ketoprofen, flurbiprofen, meloxicam, flosulide or nabumetone,
- wherein said NSAID is a potent inhibitor of PGHS-2 and wherein said NSAID possesses a selectivity for inhibiting PGHS-2 over PGHS-1 of at least 100 fold as measured by the ratio of IC50 for the inhibition of PGHS-2 to the IC50 for the inhibition of PGHS-1 in a microsomal assay, said assay conducted by measuring the amount of prostaglandin E2 synthesized in the presence of arachidonic acid, PGHS-2 or PGHS-1 enzyme and said NSAID, and wherein said assay comprises the steps of:
- (1) incubating said NSAID with the microsome expressing PGHS-2 or PGHS-1 enzyme for about 10 to 20 minutes prior to the addition of arachidonic acid, and
- (2) conducting said assay with arachidonic acid at a concentration of about 10 μM,
- wherein said NSAID possesses a potency for the inhibition of PGHS-2 of about 1 μM or less as measured by the IC50 or the inhibition of PGHS-2 in the microsomal assay, and
- wherein the microsomal assay is the CHAPS-solubilized recombinant PGHS-1 or PGHS-2 expressing insect cell membrane assay.
A method of retarding or preventing the appearance of the capacity of an adenoma to invade the basement membrane of the submucosal issue of the colon in a patient in need thereof comprising administering to said patient a non-toxic therapeutically effective amount of an NSAID, with the proviso that said NSAID is not, aspirin, ibuprofen, indomethacin, sulindac, dolobid, diclofenac, naproxen, piroxicam, etodolac, ketoprofen, flurbiprofen, meloxicam, flosulide or nabumetone,
- wherein said NSAID is a potent inhibitor of PGHS-2 and wherein said NSAID possesses a selectivity for inhibiting PGHS-2 over PGHS-1 of at least 100 fold as measured by the ratio of IC50 for the inhibition of PGHS-2 to the IC50 for the inhibition of PGHS-1 in a microsomal assay, said assay conducted by measuring the amount of prostaglandin E2 synthesized in the presence of arachidonic acid, PGHS-2 or PGHS-1 enzyme and said NSAID, and wherein said assay comprises the steps of:
- (1) incubating said NSAID with the microsome expressing PGHS-2 or PGHS-1 enzyme for about 10 to 20 minutes prior to the addition of arachidonic acid, and
- (2) conducting said assay with arachidonic acid at a concentration of about 10 μM,
- wherein said NSAID possesses a potency for the inhibition of PGHS-2 of about 1 μM or less as measured by the IC50 for the inhibition of PGHS-2 in the microsomal assay, and
- wherein the microsomal assay is the CHAPS-solubilized recombinant PGHS-1 or PGHS-2 expressing insect cell membrane assay.
A method of preventing colonic adenomas in a patient need thereof comprising administering to said patient a non-toxic therapeutically effective amount of an NSAID, with the proviso that, said NSAID is not aspirin, ibuprofen, indomethacin, sulindac, dolobid, diclofenac, naproxen, piroxicam, etodolac, ketoprofen, flurbiprofen, meloxicam, flosulide or nabumetone,
- wherein said NSAID possesses a selectivity for inhibiting PGHS-2 over PGHS-1 of at least 100 fold as measured by the ratio of the IC50 for the inhibition of PGHS-2 to the IC50 for the inhibition of PGHS-1 in a whole cell or microsomal assay, said assay conducted by measuring the amount o prostaglandin E2 synthesized in the presence of arachidonic acid, PGHS-2 or PGHS-1 enzyme and said NSAID, and wherein said assay comprises the steps of:
- (1) incubating said NSAID with the cell or microsome expressing PGHS-2 or PGHS-1 enzyme for about 10 to 20 minutes prior to the addition of arachidonic acid, and
- (2) conducting said assay with arachidonic acid at a concentration of about 10 μM.
Dependencies are inferred from the claim text.