Inhibition of tumor progression and neoangiogenesis using cyclic RGD-peptides in a chemically induced colon carcinoma in rats

TY - JOUR

T1 - Inhibition of tumor progression and neoangiogenesis using cyclic RGD-peptides in a chemically induced colon carcinoma in rats

AU - Haier, Jörg

AU - Goldmann, Ulrike

AU - Hotz, Birgit

AU - Runkel, Norbert

AU - Keilholz, Ulrich

PY - 2002

Y1 - 2002

N2 - Integrins are cell surface molecules that mediate cell adhesion, but are also important regulators of tumor cell interactions with their microenvironment, tumor cell survival and growth. In addition, the alpha(v)beta3-integrins appear to be critical for microvessel formation in tumor-induced neoangiogenesis. The present study is the first to investigate the effects of therapeutic alpha(v)beta3-integrin inhibition in a chemically induced tumor model that largely resembles human colon carcinomas. Tumor induction was performed in 47 male Sprague-Dawley rats using 1,2 dimethylhydrazin (21 mg/kg) twice a week. After 20 weeks of tumor induction, 100% of the animals developed adenocarcinomas with a median of 13.5 macroscopic tumor nodules (range 12-17), but no distant metastases. During further tumor induction for an additional 10 weeks, rats were treated three times/week with (a) 15 mg/kg RGDfV-peptide that can block vitronectin and fibronectin receptors; (b) an equimolar amount of an ineffective cyclic control peptide; or (c) with equimolar amounts of a linear RGDS-peptide. At the end of this treatment period, rats were sacrificed, and tumor load was quantified macroscopically and confirmed by histological examination. For investigation of the involvement of tumor-induced neoangiogenesis microvessel, density was determined using CD31-immunostaining. After 30 weeks, control animals (group B) had 5-18 tumors (median 14.5). If rats were treated with RGDfV-peptide (group A), the number of tumor nodules was significantly reduced (P < 0.005) to a median of seven macroscopic tumors (range 2-10 tumors), which also represented a significant reduction (P < 0.005) compared with prior to treatment. Application of noncylic RGDS-peptides (group C) did not affect the number of tumor nodules (median 18; range 10-30 tumors). The diameters of tumor nodules were comparable (3.2-6.1 mm) in animals of all groups. In addition, microvessel density was significantly (P < 0.05) reduced in tumors in group A compared to control rats. The major side effect in the treatment group was increased susceptibility to respiratory infections. Our results demonstrate that alpha(v)beta3-integrin-receptor inhibition appears to be a therapeutic strategy for colorectal cancer. In our therapeutic model, late onset of treatment with integrin-blocking peptides resulted in an inhibition of tumor growth and a reduced tumor load which appeared to be mediated, at least in part, by inhibition of neoangiogenesis.

AB - Integrins are cell surface molecules that mediate cell adhesion, but are also important regulators of tumor cell interactions with their microenvironment, tumor cell survival and growth. In addition, the alpha(v)beta3-integrins appear to be critical for microvessel formation in tumor-induced neoangiogenesis. The present study is the first to investigate the effects of therapeutic alpha(v)beta3-integrin inhibition in a chemically induced tumor model that largely resembles human colon carcinomas. Tumor induction was performed in 47 male Sprague-Dawley rats using 1,2 dimethylhydrazin (21 mg/kg) twice a week. After 20 weeks of tumor induction, 100% of the animals developed adenocarcinomas with a median of 13.5 macroscopic tumor nodules (range 12-17), but no distant metastases. During further tumor induction for an additional 10 weeks, rats were treated three times/week with (a) 15 mg/kg RGDfV-peptide that can block vitronectin and fibronectin receptors; (b) an equimolar amount of an ineffective cyclic control peptide; or (c) with equimolar amounts of a linear RGDS-peptide. At the end of this treatment period, rats were sacrificed, and tumor load was quantified macroscopically and confirmed by histological examination. For investigation of the involvement of tumor-induced neoangiogenesis microvessel, density was determined using CD31-immunostaining. After 30 weeks, control animals (group B) had 5-18 tumors (median 14.5). If rats were treated with RGDfV-peptide (group A), the number of tumor nodules was significantly reduced (P < 0.005) to a median of seven macroscopic tumors (range 2-10 tumors), which also represented a significant reduction (P < 0.005) compared with prior to treatment. Application of noncylic RGDS-peptides (group C) did not affect the number of tumor nodules (median 18; range 10-30 tumors). The diameters of tumor nodules were comparable (3.2-6.1 mm) in animals of all groups. In addition, microvessel density was significantly (P < 0.05) reduced in tumors in group A compared to control rats. The major side effect in the treatment group was increased susceptibility to respiratory infections. Our results demonstrate that alpha(v)beta3-integrin-receptor inhibition appears to be a therapeutic strategy for colorectal cancer. In our therapeutic model, late onset of treatment with integrin-blocking peptides resulted in an inhibition of tumor growth and a reduced tumor load which appeared to be mediated, at least in part, by inhibition of neoangiogenesis.

KW - Animals

KW - Carcinogens

KW - Cell Division

KW - Colonic Neoplasms

KW - Dimethylhydrazines

KW - Disease Progression

KW - Male

KW - Neovascularization, Pathologic

KW - Oligopeptides

KW - Peptides, Cyclic

KW - Rats

KW - Rats, Sprague-Dawley

KW - Time Factors

M3 - SCORING: Journal article

C2 - 12553371

VL - 19

SP - 665

EP - 672

JO - CLIN EXP METASTAS

JF - CLIN EXP METASTAS

SN - 0262-0898

IS - 8

ER -