**6. References**


PDE-5 inhibitors including sildenafil, vardenafil and tadalafil are safe and efficacious firstline on-demand agents for the treatment of erectile dysfunction (Boolell *et al.*, 1996;Porst *et al.*, 2001). Their mechanism of action involves inhibition of the PDE-5 enzyme and resulting increase in cGMP and smooth muscle relaxation in the penis. Their target enzyme, PDE-5 is expressed in several tissues throughout the human body, including the pulmonary and systemic vasculature, hypertrophied myocardium and cancer cells. Preclinical studies have demonstrated that PDE-5 inhibitors have powerful cardioprotective effect in the setting of I/R injury, pressure overload-induced hypertrophy, heart failure and DOX-induced cardiomyopathy. The effects of PDE-5 inhibitors on the pulmonary circulation and hypertrophied right ventricle have made these agents first-line therapy for many patients with pulmonary hypertension. Several reports have indicated that PDE-5 inhibitors improve erectile function following radiation therapy or post-radical prostatectomy in prostate cancer patients. Recent research from our laboratory has reported provocative findings that **sildenafil is both a powerful sensitizer of DOX-induced killing of prostate cancer and provides concurrent cardioprotective benefit (Das** *et al.***, 2010).** Moreover, sildenafil and vardenafil have been shown to block or reverse the drug efflux function of the ABC transporters, thereby suggesting that sildenafil can be used as a modulator of ABCB1 and ABCG2 to reverse MDR in cancer cells. Considering the well-established safety profile of PDE-5 inhibitors, clinical studies are needed to fully exploit the beneficial effect of the combination treatment of anti-tumor agents such as DOX with the PDE-5 inhibitors as a therapeutic tool in prostate cancer patients. Also, further studies are needed to gain in depth understanding of the molecular mechanisms by which PDE-5 inhibitors increase the efficacy

This work was supported in part by National Institutes of Health Grants HL51045, HL59469,

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**4. Concluding comments and future perspective** 

of chemotherapeutic agents.

**5. Acknowledgment** 

and HL79424 (to R.C.K).

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**14** 

Thomas H. Brill

*Germany* 

**Entering a New Era – Prostate Cancer** 

As cancer is estimated to cause 1,500,000 deaths in Europe and more than 500,000 alone in the US each year (Ferlay et al., 2007; Jemal et al., 2010) newer strategies are needed to improve current treatment success rates. The role of the immune system is designated cancer immunosurveillance as it limits tumor growth (Dunn et al., 2002). This biological principle has been deduced from clinical observations in human as if veterinary cancer patients and has also been proved experimentally in immunodeficient mice characterized by a high incidence of tumors (Shankanan et al., 2001). The evidence on the role of the immune system found in limiting tumor growth and progression is linked to observations showing a positive correlation between the presence of tumor infiltrating lymphocytes (TILs) and improved outcome in most – but not all – tumor entities studied so far; e.g. in colorectal cancer significantly higher levels of memory CD8+T-cell infiltrates are positively correlated with clinical benefit, defined as less advanced pathological stage, absence of metastatic invasion, and increased survival (Pages et al., 2005; Galon et al., 2006). Similarly, the presence of TILs has been associated with decreased tumor cells in the draining lymph nodes of cervical cancer patients limiting the risk of metastatic progression (Piersma et al., 2007). In lung carcinoma patients, increasing numbers of TILs have also been shown to significantly improve disease-specific survival (Al-Shibli et al., 2008). PCa glands are also frequent diffusely infiltrated (CD4+T-cells as if CD8+T-cells) so suggesting that PCa may be immunogenic but the correlation of these findings to clinical data is not that clear as in other tumor entities (McArdle et al., 2004; Zhang et al., 2006). Altogether, these observations support the immunosurveillance hypothesis and form the rationale to use the immune system to control tumor burden by vaccine-based interventions against cancer relying on the stimulation of an effective antitumor immune response in the cancer patient and resulted recently in labelling "avoiding immune destruction" as an emerging hallmark of cancer by the scientific community (Hanahan & Weinberg, 2011). The therapeutic cancer vaccine definition as given by the National Cancer Institute (NCI) is: vaccines, which are intended to treat already existing cancers by strengthening the body´s natural defences against cancer. But it is of great importance to notice the two paradoxical roles the immune system has in cancer: while at the one hand various components of the immune response – innate as if adaptive – are able to mediate cancer cell destruction, at the other hand specific types of

**1. Introduction** 

**Immuno-Therapy After the FDA** 

**Approval for Sipuleucel-T** 

*Technische Universität München (TUM)* 

