Apoptosis-mediated cytotoxic effects of ibandronic acid on hormone- and drug-refractory prostate cancer cells and human breast cancer cells.

Over 80% of patients with advanced breast and prostate cancer ultimately develop bone metastases. Ibandronic acid has proven efficacy for treatment of bone metastasis secondary to breast cancer. This study was designed to investigate the cytotoxic and apoptotic effects of ibandronic acid on hormone- and drug-refractory prostate carcinoma DU-145 and human breast cancer MCF-7 cell lines. Cytotoxicity was evaluated using an XTT cell proliferation kit, and apoptosis was assessed by enzyme-linked immunosorbent assay (histone-DNA fragmentation) and measurement of caspase 3/7 activity. With increasing concentrations of ibandronic acid there was a dose- and time-dependent decrease in cell numbers. MCF-7 cells were more resistant than DU-145 cells (half maximal inhibitory concentrations of 122 and 90 microM, respectively). Ibandronic acid induced apoptosis in both cell lines. The study showed an apoptosis-mediated cytotoxic effect for ibandronic acid (in addition to the already known osteoclast inhibiting effect) in breast cancer patients with bone metastases; which was also observed in prostate cancer cells. Further clinical studies involving breast and prostate cancer patients with bone metastases are warranted to confirm these findings.

Targeting apoptosis in the hormone- and drug-resistant prostate cancer cell line, DU-145, by gossypol/zoledronic acid combination.

Possible synergistic cytotoxic and apoptotic effects of gossypol with zoledronic acid on DU-145 cells were explored, along with the rationale behind any observed synergism due to the different apoptotic proteins involved. XTT cell proliferation assay was used to assess the cytotoxicity, and DNA fragmentation and caspase 3/7 activity were measured to verify apoptosis. Human Apoptosis Array was used to evaluate apoptotic proteins. The synergistic cytotoxic combination treatment had a versatile effect on apoptotic proteins, through inhibition of anti-apoptotic proteins (including cIAP-1, cIAP-2, survivin, livin, claspin, p53, p21, PON-2 and heat shock proteins) and concurrently the induction of pro-apoptotic proteins (Bad, Bax, Fas, FADD, cleaved caspase-3 and p27). Both drugs had a minimal toxicity profile comparing to cytotoxic agents. Combination treatments targeting many pivotal apoptosis-related proteins may be a rationale option for treatment of prostate cancer.

Docetaxel/zoledronic acid combination triggers apoptosis synergistically through downregulating antiapoptotic Bcl-2 protein level in hormone-refractory prostate cancer cells.

Docetaxel, a semi-synthetic taxane analogue, is used effectively in the treatment of metastatic prostate cancer. Zoledronic acid, the most potent member of bisphosphonates, has shown pleiotropic anti-tumoral effects on prostate cancer cells. We have explored the possible additive/synergistic effects and the apoptotic pathways induced by combination treatment of docetaxel and zoledronic acid in hormone and drug refractory, PC-3 and DU-145 prostate cancer cells. Combination of docetaxel and zoledronic acid synergistically inhibits cell growth in PC-3 and DU-145 cells. Moreover, this effect was due to downregulation of antiapoptotic protein Bcl-2 in PC-3 and DU-145 cells. In conclusion, docetaxel/zoledronic acid combination is potentially a novel and effective approach for the treatment of prostate cancer.

Docetaxel and platinum combination chemotherapy in locally advanced or metastatic head and neck cancer.

PURPOSE: To assess the efficacy and toxicity of the docetaxel and platinum combination in patients with locoregionally advanced or metastatic squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: A total of 24 patients with metastatic or locoregionally advanced SCCHN treated with docetaxel and platinum combination chemotherapy were retrospectively reviewed. All of them had histologically proven SCCHN, measurable disease and ECOG performance status of 2 or less, and were treated with docetaxel 75 mg/m(2) as a 60 min i.v. infusion on day 1, followed by cisplatin 75 mg/m(2) or carboplatin AUC 6 as a 60 min i.v. infusion on day 1 every 3 weeks, until disease progression or unacceptable toxicity. Patients were evaluated for response, survival and toxicity. RESULTS: Seven (29%) patients showed partial response (PR) and 1 (4%) complete response (CR) for an overall response rate of 33%. Twelve (50%) patients had stable disease (SD). Disease control rate was 83%. The median follow-up time was 26.4 months (range 2-127), the median time to progression 16 months (range 2-20), and the median overall survival 19 months (range 2-22). Grade 3-4 hematologic toxicity occurred in 13 (54%) patients. Febrile neutropenia was seen in 5 (21%) patients. CONCLUSION: Docetaxel plus cisplatin or carboplatin is an effective regimen with acceptable safety profile for palliation of locally advanced or metastatic SCCHN.

Pegylated liposomal doxorubicin in heavily pretreated epithelial ovarian cancer patients.

PURPOSE: While most patients with ovarian cancer respond to first-line treatment, 50-75% of these patients will eventually relapse. Pegylated liposomal doxorubicin (PLD) is an active agent indicated for the treatment of patients with disease that is refractory to both paclitaxel- and platinum-based regimens, but skin toxicity remains the dose-limiting toxicity of the drug. The primary objective of this retrospective study was to evaluate the activity and safety of this agent in patients with heavily pretreated ovarian cancer. PATIENTS AND METHODS: Patients with platinum-refractory/ resistant, paclitaxel-pretreated epithelial ovarian carcinoma were treated with PLD 50 mg/m2 in 4-week courses until disease progression or unacceptable toxicity. All patients had progressive disease (PD) before starting PLD. Primary endpoints were response rate, progression free survival (PFS) and toxicity and secondary endpoints duration of response (DOS) and overall survival (OS). RESULTS: Seventeen heavily pretreated patients (median number of previous chemotherapy regimens 3, range 1-5) with taxane- and platinum-refractory disease were analysed. No complete response (CR) was achieved, while 3 (17%) partial responses (PR) and 2 (11%) cases with stable disease (SD) were observed. The median PFS was 15 weeks (range 10-21) and median OS 32 weeks (range 16-47). Palmar plantar erythrodysesthesia (PPE) occurred in 4 (23%) patients and was of grade 4 in 1 (6%) patient. Stomatitis occurred in 3 (17%) patients and was grade 3 in 1 (6%) patient. Grade 3-4 neutropenia occurred in only 2 (12%) patients. No febrile neutropenia was encountered. CONCLUSION: Pegylated liposomal doxorubicin is an active and tolerable agent in heavily pretreated epithelial ovarian cancer patients.

Efficacy and safety of bevacizumab plus capecitabine and irinotecan regimen for metastatic colorectal cancer.

Recent phase III trials have proven the fact that adding bevacizumab to irinotecan plus infusional 5-fluorouracil (5-FU)/leucovorin (LV) should be preferred as a first-line treatment for metastatic colorectal cancer (mCRC). But, since the data regarding bevacizumab administered together with capecitabin, an oral fluoropyrimidine, and irinotecan in patients with mCRC is limited, we aimed to analyse the efficacy and safety of bevacizumab with capecitabine plus irinotecan (BEV-CAPIRI) regimen in mCRC patients. Records of patients treated with BEV-CAPIRI regimen between January 2005 and March 2008 were reviewed. Efficacy data regarding response rates (RR) as well as safety data were collected. Progression free survival (PFS) and overall survival (OS) analyses were done by using the Kaplan-Meier method. A total number of 53 metastatic colorectal cancer patients were treated with BEV-CAPIRI regimen. The median age of this population was 57.3 +/- 11.5 (range 29-78). The treatment was well tolerated. The RR was 43.3%, while 30.1% of the patients achieved stable disease (SD). Median PFS and OS were 12.6 +/- 1.4 and 20.6 +/- 1.7 months, respectively. However, median OS was 21.3 months for male and 14.6 months for female patients. In addition, median OS and PFS was 25.3 months and 16.2 months for the patients who received BEV-CAPIRI as first-line treatment, respectively, and for the other patients it was 15.2 months and 10.2 months, respectively. In conclusion, BEV-CAPIRI is an effective and well-tolerated alternative regimen for mCRC, leading to disease control in a vast majority of patients with mCRC.