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Modulators of arginine metabolism support cancer immunosurveillance.

Capuano G, Rigamonti N, Grioni M, Freschi M, Bellone M - BMC Immunol. (2009)

Bottom Line: Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity.Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico San Raffaele, Via Olgettina 58, 20132, Milan, Italy. giusy_capuano@hotmail.com

ABSTRACT

Background: Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity. The objective of this study was to evaluate whether accumulation of MDSC occurred in Th2 prone BALB/c and Th1 biased C57BL/6 mice bearing the C26GM colon carcinoma and RMA T lymphoma, respectively, and to investigate whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restored antitumor immunity.

Results: We report here that MDSC accumulate in the spleen and blood of mice irrespective of the mouse and tumor model used. Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.

Conclusion: Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

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Related in: MedlinePlus

Modulators of arginine metabolism do not cause loss of body weight in treated animals. Toxicity of L-NAME and sildenafil was evaluated as loss of body weight, defined as Delta % = (final weight – initial weight)/initial weight × 100. BALB/c mice challenged with C26GM cells (A) and C57BL/6 mice challenged with RMA cells (B) were weighed at day 0 and at day 9 and 15, respectively. The experimental groups are described in the legend to Fig. 3.
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Figure 4: Modulators of arginine metabolism do not cause loss of body weight in treated animals. Toxicity of L-NAME and sildenafil was evaluated as loss of body weight, defined as Delta % = (final weight – initial weight)/initial weight × 100. BALB/c mice challenged with C26GM cells (A) and C57BL/6 mice challenged with RMA cells (B) were weighed at day 0 and at day 9 and 15, respectively. The experimental groups are described in the legend to Fig. 3.

Mentions: Since chronic treatment with NO inhibitors has been reported to be associated with systemic toxicity [32], we monitored animal weight, as a measure of potential drug-related toxicity, and we found no difference between drug- and vehicle-treated mice in both strains (Fig. 4A and 4B). The respiratory apparatus (i.e., bronchial tree and lung), esophagus, kidney, suprarenal gland and liver of L-NAME treated animals were also macroscopically and microscopically investigated by an expert pathologist and found with no sign of drug-related toxicity (data not shown). Absence of drug-related toxicity in our animal models might be related to the relatively short period of treatment. Indeed, glomerulosclerosis, one of the effects of L-NAME, is usually found in animals treated for a longer period of time [33].


Modulators of arginine metabolism support cancer immunosurveillance.

Capuano G, Rigamonti N, Grioni M, Freschi M, Bellone M - BMC Immunol. (2009)

Modulators of arginine metabolism do not cause loss of body weight in treated animals. Toxicity of L-NAME and sildenafil was evaluated as loss of body weight, defined as Delta % = (final weight – initial weight)/initial weight × 100. BALB/c mice challenged with C26GM cells (A) and C57BL/6 mice challenged with RMA cells (B) were weighed at day 0 and at day 9 and 15, respectively. The experimental groups are described in the legend to Fig. 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2648942&req=5

Figure 4: Modulators of arginine metabolism do not cause loss of body weight in treated animals. Toxicity of L-NAME and sildenafil was evaluated as loss of body weight, defined as Delta % = (final weight – initial weight)/initial weight × 100. BALB/c mice challenged with C26GM cells (A) and C57BL/6 mice challenged with RMA cells (B) were weighed at day 0 and at day 9 and 15, respectively. The experimental groups are described in the legend to Fig. 3.
Mentions: Since chronic treatment with NO inhibitors has been reported to be associated with systemic toxicity [32], we monitored animal weight, as a measure of potential drug-related toxicity, and we found no difference between drug- and vehicle-treated mice in both strains (Fig. 4A and 4B). The respiratory apparatus (i.e., bronchial tree and lung), esophagus, kidney, suprarenal gland and liver of L-NAME treated animals were also macroscopically and microscopically investigated by an expert pathologist and found with no sign of drug-related toxicity (data not shown). Absence of drug-related toxicity in our animal models might be related to the relatively short period of treatment. Indeed, glomerulosclerosis, one of the effects of L-NAME, is usually found in animals treated for a longer period of time [33].

Bottom Line: Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity.Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

View Article: PubMed Central - HTML - PubMed

Affiliation: Cancer Immunotherapy and Gene Therapy Program, Istituto Scientifico San Raffaele, Via Olgettina 58, 20132, Milan, Italy. giusy_capuano@hotmail.com

ABSTRACT

Background: Tumor-associated accrual of myeloid derived suppressor cells (MDSC) in the blood, lymphoid organs and tumor tissues may lead to perturbation of the arginine metabolism and impairment of the endogenous antitumor immunity. The objective of this study was to evaluate whether accumulation of MDSC occurred in Th2 prone BALB/c and Th1 biased C57BL/6 mice bearing the C26GM colon carcinoma and RMA T lymphoma, respectively, and to investigate whether N(G) nitro-L-arginine methyl ester (L-NAME) and sildenafil, both modulators of the arginine metabolism, restored antitumor immunity.

Results: We report here that MDSC accumulate in the spleen and blood of mice irrespective of the mouse and tumor model used. Treatment of tumor-bearing mice with either the phosphodiesterase-5 inhibitor sildenafil or the nitric-oxide synthase (NOS) inhibitor L-NAME significantly restrained tumor growth and expanded the tumor-specific immune response.

Conclusion: Our data emphasize the role of MDSC in modulating the endogenous tumor-specific immune response and underline the anti-neoplastic therapeutic potential of arginine metabolism modulators.

Show MeSH
Related in: MedlinePlus