Synthesis and pharmacological screening of a large library of 1,3,4-thiadiazolines as innovative therapeutic tools for the treatment of prostate cancer and melanoma.

Antimitotic agents are widely used in cancer chemotherapy but the numerous side effects and the onset of resistance limit their clinical efficacy. Therefore, with the purpose of discovering more selective and efficient anticancer agents to be administered alone or in combination with traditional drugs, we synthesized a large library of 1,3,4-thiadiazoline analogues, maintaining the pharmacophoric structure of an antiproliferative compound known as K858: this is a new inhibitor of kinesin Eg5, able to induce the mitotic arrest in colorectal cancer cells and in xenograft ovarian cancer cells. We screened 103 compounds to assess their antiproliferative activity on PC3 prostate cancer cell line.

Beyond the Immune Suppression: The Immunotherapy in Prostate Cancer.

Prostate cancer (PCa) is the second most common cancer in men. As well in many other human cancers, inflammation and immune suppression have an important role in their development. We briefly describe the host components that interact with the tumor to generate an immune suppressive environment involved in PCa promotion and progression.

Effect of Serenoa repens (Permixon®) on the expression of inflammation-related genes: analysis in primary cell cultures of human prostate carcinoma.

Background: To analyze the expression at basal level of inflammation-related cytokines and chemokines and the activation status of the NF-κB pathway, together with the proliferation and apoptosis indexes in two widely used in vitro tumor models, the androgen-dependent human Prostate Cancer (PC) cell line LNCaP and the androgen-independent PC3 , and in primary cultures of human PC cells. To assess in these models and primary cultures, the effects of Serenoa repens (LSESr, Permixon®) on proliferation/apoptosis ratio, inflammation-related genes expression and NF-κB pathway activation.

Methods: The expression of IL-6, CCL-5, CCL-2, COX-1, COX-2, iNOS inflammation-related genes has been evaluated at the mRNA level in two in vitro human PC models (LNCaP and PC3 cell lines) and in 40 independent human prostatic primary cultures obtained from PC patients undergoing radical prostatectomy.

Circulating tumour cells lacking cytokeratin in breast cancer: the importance of being mesenchymal.

Circulating tumour cells (CTCs) are independent predictor of prognosis in metastatic breast cancer. Nevertheless, in one third of patients, circulating tumour cells are undetected by conventional methods. Aim of the study was to assess the prognostic value of circulating tumour cells expressing mesenchymal markers in metastatic breast cancer patients.

Prognostic significance of survivin-expressing circulating tumour cells in T1G3 bladder cancer.

Objective: To evaluate the prognostic significance of survivin in tumour tissues and that of survivin-expressing circulating tumour cells (CTCs) in T1G3 bladder tumours, as the prognosis of T1G3 bladder cancer is highly variable and unpredictable from clinical and pathological prognostic factors.

Patients And Methods: The study included 54 patients with T1G3 non-muscle-invasive bladder cancer. Additional inclusion criteria were: tumour size <3 cm, absence of carcinoma in situ and multifocality.

Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelial tumors.

The prognostic value associated with the detection of circulating tumor cells (CTCs) in metastatic breast cancer by the CellSearch technology raise additional issues regarding the biological value of this information. We postulated that a drug-resistance profile of CTCs may predict response to chemotherapy in cancer patients and therefore could be used for patient selection. One hundred 5 patients with diagnosis of carcinoma were enrolled in a prospective trial.

A chemosensitivity test to individualize intravesical treatment for non-muscle-invasive bladder cancer.

Objective: To describe the design of a new chemosensitivity assay based on the expression of genes involved in the resistance to standard intravesical regimens, to allow individualization of therapy for high-risk non-muscle-invasive bladder cancer.

Patients And Methods: To date, 35 patients with high-risk non-muscle-invasive bladder cancer have been enrolled, all candidates for transurethral resection of the bladder (TURB) followed by intravesical treatment. The intravesical regimen was chosen according to the risk profile of each patient.

Failure of apoptosis and activation on NFkappaB by celecoxib and aspirin in lung cancer cell lines.

Recent studies have demonstrated that antineoplastic activity of Cox-2 inhibitors may depend on targets other than Cox: among those, nuclear factor kappaB (NFkappaB) seems the most promising. Although preclinical studies have suggested that aspirin and Cox-2 inhibitors may influence the progression of lung cancer, the molecular mechanisms of these protective effects in this tumor type has not been fully elucidated. We investigated the effects of celecoxib and aspirin in the induction of apoptosis and in the ability to activate NFkappaB in three non-small cell lung cancer cell lines.

Gemcitabine-induced apoptosis in 5637 cell line: an in-vitro model for high-risk superficial bladder cancer.

Recent data suggest that new treatment options for superficial bladder cancer are necessary, owing to the high recurrence rate after conventional treatment, especially in T1G3 and Bacillus Calmette-Guerin-refractory patients. Phase I and II studies have demonstrated that gemcitabine may represent a candidate for intravesical therapy in superficial bladder cancer. Despite clinical trials, the in-vitro cytotoxic and proapoptotic effects of gemcitabine have been poorly investigated.

Tenascin C and epidermal growth factor receptor as markers of circulating tumoral cells in bladder and colon cancer.

Tenascin C has been recently suggested as a tumor marker, however, its levels in serum has been evaluated only in patients with head and neck cancer and melanoma. In this study, we investigated Tenascin C expression in blood samples from colorectal and bladder cancer patients, compared to that of epidermal growth factor receptor (EGFR), a known circulating tumor marker in these cancer types. RT-PCR specific for Tenascin C and EGFR was performed on RNAs extracted from blood samples of 60 patients affected by colon or bladder cancer.

Comparison of extracellular matrix and apoptotic markers between benign lesions and carcinomas in human breast.

The expression of the extracellular matrix-related genes, such as fibronectin, laminin and tenascin C, and apoptosis-related genes, such as bax, bcl2 and survivin, was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and by immunohistochemistry in normal breast tissue and benign and malignant breast tumors and then correlated to several clinical parameters: estrogen and progesterone receptors, Ki67, ErbB2, tumor size, lymph node status and grading. Seventy-three breast tissue samples were examined. After RNA extraction, an RT-PCR was performed to detect fibronectin, laminin, tenascin C, bax, bcl2 and survivin gene expression.

UDP-glucuronosyltransferases 1A expression in human urinary bladder and colon cancer by immunohistochemistry.

UDP-glucuronosyltrasferases (UGTs) are detoxifying enzymes, which convert endogenous substrates, dietary constituents and potential carcinogens to inactive hydrophilic glucuronides. Although the liver is considered the most important organ for glucuronidation, UGTs are also expressed in extrahepatic tissues. Since UGTs may be important to protect cells from cancer in organs naturally exposed to potential carcinogens such as smoking and diet derivatives, we investigated the UGT expression in normal and malignant tissues from urinary bladder and large intestine.

Raloxifene modulates interleukin-6 and tumor necrosis factor-alpha synthesis in vivo: results from a pilot clinical study.

Raloxifene (RAL), a selective estrogen receptor modulator, is indicated for the prevention and treatment of postmenopausal osteoporosis. RAL, by decreasing bone turnover, prevents bone loss and microarchitecture damage, reducing the incidence of osteoporotic fractures. Our previous in vitro data demonstrated that RAL modulates osteoclast activity by, at least in part, an IL-6- and TNF-alpha-dependent mechanism.

Guanine nucleotide depletion triggers cell cycle arrest and apoptosis in human neuroblastoma cell lines.

Mycophenolic acid (MPA) specifically inhibits inosine-5'-monophosphate dehydrogenase, the first committed step toward GMP biosynthesis. In its morpholinoethyl ester pro-drug form it is one of the most promising immunosuppressive drugs recently developed. The aim of the present study was to investigate the in vitro effects of MPA, at concentrations readily attainable during immunosuppressive therapy, on 3 human neuroblastoma cell lines (LAN5, SHEP and IMR32).

Persistence of epidermal growth factor receptor and interleukin 10 in blood of colorectal cancer patients after surgery identifies patients with high risk to relapse.

Purpose: Despite the great number of studies performed to detect circulating markers of disease progression in colorectal cancer, few have shown a clinical use; among those, epidermal growth factor receptor (EGFR) and, more recently, interleukin (IL)-10. In this article, we sought to investigate how primary surgery could affect expression levels of EGFR, IL-6, and IL-10 in blood from colorectal cancer patients.

Experimental Design: We investigated by reverse transcriptase-PCR assay the expression at mRNA level of EGFR, IL-6, and IL-10 in blood samples taken from 56 colorectal cancer patients.

Prognostic significance of reverse transcriptase-polymerase chain reaction-negative sentinel nodes in malignant melanoma.

Background: Polymerase chain reaction (PCR) is a molecular biology technique that can detect a single metastatic cell in 10(6) to 10(7) normal cells. Its use has been proposed as an additional new method for the detection of malignant melanoma nodal metastases in the sentinel lymph node (SLN) to improve the detection rate guaranteed so far by standard histology (hematoxylin and eosin; H&E) and immunohistochemistry (IHC).

Methods: Since October 1995, 137 patients with primary cutaneous melanoma (Breslow thickness,.

Survivin, bcl-2, bax, and bcl-X gene expression in sentinel lymph nodes from melanoma patients.

Purpose: The expression of apoptosis-related genes, such as survivin, bcl-2, bcl-X, and bax, has been evaluated by reverse transcriptase polymerase chain reaction (RT-PCR) and by immunohistochemistry in sentinel lymph nodes (SLNs) from melanoma patients and then correlated to the outcome of patients.

Patients And Methods: Thirty-six SLNs were examined. After RNA extraction, an RT-PCR followed by Southern blot hybridization was performed to detect survivin, bcl-2, bcl-X, and bax mRNA.

Detection of CK19, CK20 and EGFR mRNAs in peripheral blood of carcinoma patients: correlation with clinical stage of disease.

Expression of genes such as cytokeratin 19 (CK19), cytokeratin 20 (CK20) and epidermal growth factor receptor (EGFR) has been investigated at mRNA level in peripheral blood of carcinoma patients to detect the presence of circulating tumor cells (CTC). We performed this study because recent literature emphasizes that the importance of CK19, 20 and EGFR mRNAs in CTC as prognostic factors remains unclear especially for breast, head and neck and colon cancer patients. Reverse transcriptase polymerase chain reaction (RT-PCR) followed by Southern blot hybridization was performed in blood samples from 47 subjects (12 colorectal, 15 head and neck and 20 breast carcinoma patients), as well as in 35 healthy donors.