enalapril and Colonic-Neoplasms

Prostaglandin (PG) E(2), a cyclooxygenase (COX) product, and angiotensin II are endogenous and have physiological roles in the body. On the other hand, an inducible isoform of COX (COX-2), insulin-like growth factor (IGF) II, and IGF-I receptor (IGF-IR) are up-regulated in colon carcinoma and might have crucial roles in tumor growth and invasion. The aim of the present study was to investigate the effects of COX-2 inhibitor and drugs blocking the biological activities of angiotensin II [angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs)] on IGF-IR expression and tumor growth in vivo. We also investigated the effects of PGE(2), a major COX-2 product, in cancer cells and the effects of angiotensin II on IGF-IR expression and the underlying mechanism of action. In in vivo studies, tumor growth and IGF-IR expression were investigated in Colon 26 cells inoculated into BALB/c mice. In in vitro studies, the effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on IGF-IR expression were analyzed in three colon cancer cell lines (Colon 26, HCA-7, and LS174T). IGF-II-induced cell growth and invasion were analyzed in Colon 26 cells in the presence and absence of NSAIDs (indomethacin and celecoxib) and angiotensin II. Celecoxib at the lowest effective dose for suppression of PG production (3 mg/kg) or an ACE inhibitor/ARB alone did not have a significant effect as compared with controls, although a high dose of celecoxib (>20 mg/kg) suppressed tumor growth. On the other hand, combination therapy with these two categories of drugs significantly reduced tumor growth in vivo. Treatment with both celecoxib and an ACE inhibitor/ARB decreased IGF-IR expression levels in inoculated tumor cells. In in vitro studies, NSAIDs reduced IGF-IR expression in a dose-dependent manner in all three cell lines. NSAIDs also inhibited IGF-II-stimulated growth and invasion in a dose-dependent manner. PGE(2) or angiotensin II treatment reversed the NSAID-induced down-regulation of IGF-IR expression, growth, and invasion. PGE(2) and angiotensin II induced Akt phosphorylation, and LY294002 or wortmannin inhibited PGE(2)- or angiotensin II-induced IGF-IR expression, indicating that PGE(2) and angiotensin II both regulate IGF-IR expression by the same Akt/phosphatidylinositol-3 pathway. Thus, combination therapy with NSAIDs and ACE inhibitors targeting IGF-IR might be a novel and potentially promising strategy for the chemoprevention of colon cancer.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Cell Division; Colonic Neoplasms; Cyclooxygenase 1; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dinoprostone; Drug Synergism; Enalapril; Humans; Indomethacin; Isoenzymes; Male; Membrane Proteins; Mice; Prostaglandin-Endoperoxide Synthases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyrazoles; Receptor, IGF Type 1; Sulfonamides

Induced hypertension and kininase inhibition can enhance tumor targeting of radiolabeled monoclonal antibody (MAb) by altering tumor circulation. This study investigated the effect of this manipulation on the antitumor efficacy of radioimmunotherapy (RIT).. Mice bearing human colon cancer xenografts were administered 2.0 microg/kg/min of angiotensin II (AT-II) for 1 h and 30 microg of a kininase inhibitor, enalapril maleate, before the administration of 3.7 MBq (131)I-A7, an IgG1 against 45-kDa glycoprotein on colorectal cancer, and tumor growth was observed thereafter. The mechanism of the manipulation effect was investigated by estimation of the tissue absorbed dose and radioluminography of tumors.. The pharmacologic manipulation with AT-II and enalapril improved the tumor quadrupling time (Tq) of 3.7 MBq RIT from 24.3 +/- 2.75 d to 33.1 +/- 2.83 d (P < 0.05). Addition of this manipulation made 3.7 MBq RIT as effective as 9.25 MBq RIT alone (Tq, 37.2 +/- 2.97 d). Dose estimation showed that the manipulation increased the tumor absorbed dose 1.55-fold without affecting the doses to normal tissues. Uniform intratumoral distribution in the manipulated tumors was shown by radioluminography.. Larger and more uniform tumor radiation produced by this pharmacologic manipulation can benefit RIT with (131)I-MAb.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Monoclonal; Colonic Neoplasms; Enalapril; Female; Humans; Iodine Radioisotopes; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Radioimmunotherapy; Radionuclide Imaging; Radiotherapy Dosage; Vasoconstrictor Agents

Induced hypertension with angiotensin II (AT-II) and the inhibition of kininase with enalapril maleate may increase the tumor targeting of radiolabeled monoclonal antibodies (MAbs). We previously found that short-period infusion of 2.0 microg/kg/min of AT-II enhanced tumor targeting of MAb without an impact on normal tissue distribution. In this study, we aimed to optimize the manipulation with these agents, and examine the possible mechanism of their effects on MAb distribution. Effect of the manipulation on tissue circulation was assessed in mice bearing colon cancer xenografts by 201Tl and 99mTc-human serum albumin (HSA) as markers of tissue blood flow and tissue blood volume and/or vascular permeability. A dose finding study of enalapril ranging from 3 to 300 microg showed that 30 microg of enalapril in combination with AT-II infusion produced the best improvement in tumor uptake of 99Tc-HSA without altering 201Tl distribution, suggesting that the increase of vascular permeability was caused by enalapril. AT-II infusion for longer than 1 h affected renal blood flow and caused subcutaneous edema. Tumor uptake of (111)In-A7, a murine IgG1, was 1.62-fold improved 72 h postinjection (P < 0.001) and intratumoral distribution became uniform with 2.0 microg/kg/min of AT-II for 1 h and 30 microg of enalapril. Vessels in manipulated tumors were distended even 48 h after the cessation of AT-II infusion. In conclusion, it was suggested that persistent distension of tumor vessels and the increase of diffusive extravasation of MAb caused by short-period-induced hypertension and inhibition of bradykinin degradation produced favorable effect for the MAb distribution in tumors.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Autoradiography; Colonic Neoplasms; Enalapril; Extravasation of Diagnostic and Therapeutic Materials; Female; Mice; Mice, Inbred BALB C; Mice, Nude; Radioimmunotherapy; Serum Albumin; Thallium Radioisotopes; Tissue Distribution; Transplantation, Heterologous

The effect of kininase II inhibitor, enalapril, on the delivery of monoclonal antibody A7 to the targeted tumor was investigated using athymic mice bearing human colon cancer, SW1116. Enalapril alone, which enhances tumor vascular permeability through the kinin-generating cascade, did not increase the uptake of 125I-labeled A7 (125I-A7) in SW1116 due to the systemic hypotension induced by its inhibitory effect on angiotensin converting enzyme. However, with combined angiotensin II (AT-II) and enalapril treatment, a 2-fold increase in the accumulation of 125I-A7 was seen when compared to A7 alone. This marked increase was presumably due to increased tumor vascular permeability induced by enalapril combined with the absence of hypotension due to the actions of AT-II. This approach might be useful in radioimmunodetection and immunotargeting chemotherapy using monoclonal antibody.

Topics: Angiotensin II; Animals; Antibodies, Monoclonal; Blood Pressure; Capillary Permeability; Colonic Neoplasms; Enalapril; Female; Humans; Mice; Mice, Inbred BALB C; Mice, Nude