Bladder cancer is the fifth most common cancer in adult patients. Two-thirds of patients have superficial tumors and their treatment is conservative. Nevertheless, 30% of superficial tumors become infiltrative and represent a third of tumors at initial diagnosis. Overall mortality from bladder cancer is 30%. Important molecular events may explain the carcinogenesis and evolution of these tumors. Infiltrating bladder cancers are currently treated by radical cystectomy. Neoadjuvant chemotherapy has demonstrated a positive impact on patients' outcomes before cystectomy. Adjuvant chemotherapy after cystectomy is currently being studied in an international randomized trial. Patients with advanced disease are treated by chemotherapy with palliative intentions. Two regimens are standard: the combination of methotrexate, vinblastine, adriamycin and cisplatin, and the combination of gemcitabine and cisplatin. The addition of paclitaxel to the latter regimen is the subject of ongoing study. Only a few patients have long-term nonevolutive disease. Research must be focused on the combination of chemotherapy and targeted drugs directed through gene methylation, cytokine-receptor activation and signaling pathways.
"Until now, even after successful radical cystectomy and lymph node dissection, about 50% of bladder cancer patients eventually show recurrence and have poor survival . For more than 30 years, there have been many efforts to reduce the recurrence of high-risk bladder cancer after curative surgery, however, numerous clinical trials failed to show conclusive evidence on the impact of adjuvant chemotherapy even by using the most toxic combination regimens . Considering these facts, blocking VEGF-C/D pathway and lymphangiogenesis could be another attractive alternative to reduce the recurrence of bladder tumor after curative radical cystectomy. "
[Show abstract][Hide abstract] ABSTRACT: Most bladder cancer patients experience lymphatic metastasis in the course of disease progression, yet the relationship between lymphangiogenesis and lymphatic metastasis is not well known. The aim of this study is to elucidate underlying mechanisms of how expanded lymphatic vessels and tumor microenvironment interacts each other and to find effective therapeutic options to inhibit lymphatic metastasis.
The orthotopic urinary bladder cancer (OUBC) model was generated by intravesical injection of MBT-2 cell lines. We investigated the angiogenesis, lymphangiogenesis, and CD11b+/CD68+ tumor-associated macrophages (TAM) by using immunofluorescence staining. OUBC displayed a profound lymphangiogenesis and massive infiltration of TAM in primary tumor and lymphatic metastasis in lymph nodes. TAM flocked near lymphatic vessels and express higher levels of VEGF-C/D than CD11b- cells. Because VEGFR-3 was highly expressed in lymphatic vascular endothelial cells, TAM could assist lymphangiogenesis by paracrine manner in bladder tumor. VEGFR-3 expressing adenovirus was administered to block VEGF-C/D signaling pathway and clodronate liposome was used to deplete TAM. The blockade of VEGF-C/D with soluble VEGF receptor-3 markedly inhibited lymphangiogenesis and lymphatic metastasis in OUBC. In addition, the depletion of TAM with clodronate liposome exerted similar effects on OUBC.
VEGF-C/D are the main factors of lymphangiogenesis and lymphatic metastasis in bladder cancer. Moreover, TAM plays an important role in these processes by producing VEGF-C/D. The inhibition of lymphangiogenesis could provide another therapeutic target to inhibit lymphatic metastasis and recurrence in patients with invasive bladder cancer.
Molecular Cancer 04/2011; 10(1):36. DOI:10.1186/1476-4598-10-36 · 4.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Etoposide is a widely used topoisomerase II inhibitor particularly useful in the clinic for treatment of disseminated tumors, including childhood leukemia. However, its use is associated with the increased risk of development of secondary acute myelogenous leukemias. The mechanism behind this is still unclear. It was hypothesized that etoposide ortho-quinone, a reactive metabolite previously shown to be generated in vitro by myeloperoxidase, the major oxidative enzyme in the bone marrow cells from which the secondary leukemias arise, might be a contributor to the development of treatment-related secondary leukemias. Experiments showed that the glutathione adduct of etoposide ortho-quinone was formed in myeloperoxidase-expressing human myeloid leukemia HL60 cells treated with etoposide, that its formation was enhanced by addition of the myeloperoxidase substrate hydrogen peroxide, and that the glutathione adduct level was dependent on myeloperoxidase. Both the normoisotopic and a stable isotope-labeled version of the glutathione adduct were synthesized. The latter was used for liquid chromatography-mass spectrometry-based quantitative analyses of the adduct formed by the cells. Discodermolide and dictyostatin are two strucuturally related natural products that possess potent microtubule stabilizing activity. Discodermolide advanced to Phase II clinical trials, but the trials were halted for unannounced reasons. Here, both agents were found to be extensively metabolized by human liver microsomes in vitro. In order to determine the metabolic soft spots in the molecules, the chemical structures of the metabolites of discodermolide and dictyostatin were elucidated by liquid chromatography-mass spectrometry. At least eight metabolites of discodermolide and six metabolites of dictyostatin were formed in human liver microsomes in vitro. The terminal diene groups on discodermolide and dictyostatin were found to be the metabolic soft spots. Results from these studies can be used in future medicinal chemistry design and synthesis work to decrease metabolic rate and improve drug metabolism and pharmacokinetic properties, therefore decreasing the doses needed and perhaps even the toxicity.
[Show abstract][Hide abstract] ABSTRACT: Toxicity assessments on patients undergoing chemotherapy or targeted molecular therapy are performed regularly by the referring oncologist. Some toxicities have radiologic manifestations (see Table 7.1). Occasionally, the radiologist is asked by the oncologist to assess for a clinically suspected toxicity that has an associated radiologic presentation. An example of this is bleomycin-induced pulmonary toxicity encountered during the treatment of metastatic germ cell tumor of the testis. Some classic chemotherapy agents and particularly the newer targeted therapies have toxicities with radiologic manifestations that are asymptomatic . Therefore the radiologist may be the first to detect these toxicities. A summary of the treatment options and radiographic presentations of the more common side effects encountered during treatment of genitourinary tumors is presented here.
Atlas of Genitourinary Oncological Imaging, 2013 edited by Ariadne M. Bach, Jingbo Zhang, 01/2013: chapter Atlas of Genitourinary Oncological Imaging: pages 231-245; Springer., ISBN: 978-1-4614-4871-6
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