Inhibition of angiogenesis by sulindac and its sulfone metabolite (FGN-1): a potential mechanism for their antineoplastic properties.
The nonsteroidal antiinflammatory drug sulindac (sulfoxide) is known to cause regression and prevent recurrence of adenomas in patients with familial adenomatous polyposis. The mechanism of action does not appear to require inhibition of prostaglandin synthesis since the sulfone metabolite of sulindac (FGN-1) retains the antineoplastic properties of sulindac but lacks inhibitory effects on cyclooxygenase, types 1 and 2. FGN-1 has been shown to induce apoptosis in a variety of tumor cell lines, and selective apoptosis of neoplastic cells has been proposed to account for its antineoplastic properties. Since angiogenesis is necessary for tumor progression and may be related to apoptosis, it is possible that inhibition of angiogenesis may also contribute to the antineoplastic properties of sulindac or FGN-1. In order to test this possibility, cells derived from several different types of human lung tumors were grafted intradermally in Balb/c mice. Sulindac sulfoxide and its sulfide and sulfone metabolites were administered for 3 days orally, in a daily dose of 0.025-0.5 mg, and angiogenesis was measured after 72 h using a previously described method. The results showed that sulindac sulfoxide and sulfone statistically inhibited angiogenesis.
Skopińska-Rózewska
E
E
Department of Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
Piazza
G A
GA
Sommer
E
E
Pamukcu
R
R
Barcz
E
E
Filewska
M
M
Kupis
W
W
Caban
R
R
Rudziński
P
P
Bogdan
J
J
Mlekodaj
S
S
Sikorska
E
E
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology*; D000328:Adult; D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D013467:Sulindac / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D013467:Sulindac; C025463:sulindac sulfone