Pazopanib: a new multiple tyrosine kinase inhibitor in the therapy of metastatic renal cell carcinoma and other solid tumors.

Angiogenesis plays a crucial role in tumor progression. Tumor angiogenesis is driven by host-derived circulating factors. Prominent among these factors is vascular endothelial growth factor (VEGF). Two basic approaches have been pursued in therapies targeting VEGF: neutralization of VEGF by antibodies or inhibition of VEGF receptor (VEGFR). VEGFR inhibition has relied on the use of small-molecular inhibitors. These drugs inhibit the tyrosine kinase activity of VEGFRs as well as other tyrosine kinases, and the term tyrosine kinase inhibitor (TKI) is used to describe this class of drugs. Pazopanib (GW786034), N(4)-(2,3-dimethyl-2H-indazol-6-yl]-N(4) - methyl-N(2)-(4-methyl-3-sulfnonamidophenyl)-2,4-pyrimidinediamine, is a novel orally bioavailable TKI that targets VEGFR1, VEGFR3, platelet-derived growth factor receptor (PDGFR)-alpha, PDGFR-beta and c-kit. Activity was observed in early clinical testing, specifically in patients with metastatic renal cell carcinoma (RCC). In subsequent phase II and phase III trials, the activity of pazopanib was comparable to other targeted agents used in the first-line therapy of metastatic RCC. Promising activity was reported in a number of other tumors, including metastatic carcinoma of the uterine cervix and differentiated carcinomas of the thyroid.

[Merkel cell skin carcinoma]. / Kozní karcinom z Merkelových bunek.

Merkel cell carcinoma is a rare tumour of the skin. It affects predominantly elderly Caucasian males on sun-exposed areas of the skin. Distinctively more frequent and at significantly lower age, its incidence is higher in immunocompromised patients. In these patients we often observe the highly aggressive course of Merkel cell carcinoma and a fatal outcome. The incidence of Merkel cell carcinoma has been rising in recent years and is more dramatic than the increased incidence of cutaneous melanoma. More than one-third of Merkel cell carcinoma patients will die from this cancer, making it twice as lethal as melanoma. The malignant transformation of Merkel cells is currently thought to be related to an infection with Merkel cell polyomavirus. In the early stage the discreet clinical picture may be contrary to extensive microscopic invasion and this seemingly benign appearance can delay diagnosis or increase the risk of insufficient tumour excision. The diagnosis is definitely confirmed by histological evaluation and immunohistochemical tests. A typical feature is the tendency of Merkel cell carcinoma to frequent local recurrence and early metastasizing into regional lymph nodes with subsequent tumour generalization. The mainstay of therapy is radical excision of the tumour and adjuvant radiotherapy targeted at the site of primary incidence and local draining lymph nodes. The efficacy of different chemotherapy protocols in Merkel cell carcinoma is limited and the median survival rate is measured in months. In the future, prophylaxis with vaccination against Merkel cell polyomavirus will hopefully be possible in high-risk patients, as well as therapeutic usage of antisense oligonucleotides or microRNAs, eventually complete Merkel cell carcinoma elimination by affecting the tumour suppressor gene Atonal homolog 1 expression. The staging of the tumour at time of diagnosis is the most important prognostic factor. In this respect, the importance of preventative skin inspection in high-risk immunocompromised patients must be stressed and suitable therapy must be indicated in suspected lesions.