Efficacy of Capecitabine and Temozolomide Regimen in Neuroendocrine Tumors: Data From the Turkish Oncology Group.

INTRODUCTION: This study aims to report the efficacy and safety of capecitabine plus temozolomide (CAPTEM) across different lines of treatment in patients with metastatic neuroendocrine tumors (NETs). METHODS: We conducted a multicenter retrospective study analyzing the data of 308 patients with metastatic NETs treated with CAPTEM between 2010 and 2022 in 34 different hospitals across various regions of Turkey. RESULTS: The median follow-up time was 41.0 months (range: 1.7-212.1), and the median age was 53 years (range: 22-79). Our results across the entire patient cohort showed a median progression-free survival (PFS) of 10.6 months and a median overall survival (OS) of 60.4 months. First-line CAPTEM treatment appeared more effective, with a median PFS of 16.1 months and a median OS of 105.8 months (median PFS 16.1, 7.9, and 9.6 months in first-, second- and ≥third-line respectively, P = .01; with median OS values of 105.8, 47.2, and 24.1 months, respectively, P = .003) In terms of ORR, the first-line treatment again performed better, resulting in an ORR of 54.7% compared to 33.3% and 30.0% in the second and third or higher lines, respectively (P < .001). Grade 3-4 side effects occurred only in 22.5% of the patients, leading to a discontinuation rate of 9.5%. Despite the differences in outcomes based on treatment line, we did not observe a significant difference in terms of side effects between the first and subsequent lines of treatment. CONCLUSIONS AND RELEVANCE: The substantial superior outcomes in patients receiving first-line CAPTEM treatment highlight its potential as an effective treatment strategy for patients with metastatic NET.

Preoperative radiotherapy with concomitant chemotherapy in extremity soft tissue sarcomas: long-term results of a single center.

PURPOSE: To assess oncological outcomes of patients receiving neoadjuvant radiochemotherapy (RCT) for soft tissue sarcoma (STS) of the extremities. METHODS: Patients who were treated with preoperative radiotherapy and concomitant chemotherapy-3 cycles of mitomycin/doxorubicin/cisplatin (MAP) or 2-4 cycles of doxorubicin/cisplatin (AP)-followed by surgery were analyzed retrospectively. Survival rates were estimated, and prognostic factors were identified. RESULTS: Between 1994 and 2017, a total of 108 patients were included. Median ages were 43 years and 51 years for patients receiving MAP and AP, respectively. The 5­year local relapse-free survival (LRFS), disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS) were 94.1, 63.6, 75.3, and 71.9%, respectively. In the multivariate analysis, significant predictors were identified as follows: de novo or R1/R2 resected tumor on admission before RCT (p = 0.017; hazard ratio [HR] 0.112, 95% confidence interval [CI] 0.019-0.675) and R0 resection after RCT (p = 0.010; HR 0.121, 95% CI 0.024-0.598) for LRFS; female gender (p = 0.042; HR 0.569, 95% CI 0.330-0.979) and liposarcoma histology (p = 0.014; HR 0.436, 95% CI 0.224-0.845) for DFS; liposarcoma histology (p = 0.003; HR 0.114, 95% CI 0.027-0.478) and AP regimen (p = 0.017; HR 0.371, 95% CI 0.165-0.836) for DSS; age ≤ 45 years (p = 0.043; HR 0.537, 95% CI 0.294-0.980) and liposarcoma histology (p = 0.006; HR 0.318, 95% CI 0.141-0.716) for OS, respectively. CONCLUSION: An increased risk for local failure seems to exist for patients with relapsed tumor on admission and having positive surgical margins after neoadjuvant RCT. Intensity of chemotherapy influenced DSS but not OS, which could be due to younger patients receiving MAP.

Combination of zoledronic acid and serine/threonine phosphatase inhibitors induces synergistic cytotoxicity and apoptosis in human breast cancer cells via inhibition of PI3K/Akt pathway.

The aim of this study was to investigate the cytotoxic and apoptotic effects of zoledronic acid (ZA) in combination with serine/threonine protein phosphatase inhibitors, calyculin-A (CA) and okadaic acid (OA), in human MCF-7 and MDA-MB-231 breast cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. DNA fragmentation and caspase-3/7 activity assays were performed to evaluate apoptosis. Activities of phosphatase 1 (PP1) and phosphatase 2A (PP2A) were measured by serine/threonine phosphatase ELISA kit. Expression levels of PI3K, p-PI3K, Akt, p-Akt, Bcl-2, p-Bcl-2, Bad, and p-Bad proteins were evaluated by Western blot analysis. Combination of ZA with either CA or OA showed synergistic cytotoxicity and apoptosis as compared to any agent alone in both MCF-7 and MDA-MB-231 breast cancer cells. Combination treatment also resulted in inhibition of both PP1 and PP2A activities. Both agents used alone or in combination did not induce significant changes in total PI3K, Akt, Bcl-2, and Bad expressions, while p-PI3K, p-Akt, p-Bcl-2, and p-Bad levels were reduced by the combination treatment as compared to agents alone. Moreover, apoptotic effect of combination treatment was significantly inhibited in the presence of LY294002, a specific PI3K inhibitor, in both breast cancer cell lines. In conclusion, synergistic apoptotic effect of the combination treatment is correlated with the block of the PI3K/Akt signal pathway in breast cancer cells.

Zoledronic acid increases cytotoxicity by inducing apoptosis in hormone and docetaxel-resistant prostate cancer cell lines.

Our aim was to investigate the possible synergistic/additive cytotoxic and apoptotic effects of combination of docetaxel and zoledronic acid (ZA), in PC-3 hormone-refractory prostate cancer cells (HRPC), as well as their docetaxel-resistant sublines. We established a docetaxel-resistant cell line (PC-3R) from PC-3 prostate cancer cells, by intermittent exposure to increasing concentrations of docetaxel in vitro. We then examined the effect of ZA and docetaxel on cell proliferation in both PC-3 and PC-3R prostate cancer cells. XTT cell proliferation assay was used to assess the cytotoxicity, and DNA fragmentation and caspase 3/7 enzyme activity were measured to verify apoptosis. According to our results, docetaxel and ZA were found to be synergistically cytotoxic and apoptotic in both PC-3 and docetaxel-resistant PC-3R cells, in a dose- and time-dependent manner. Combined treatment with docetaxel and ZA synergistically inhibited PC-3 cell growth in vitro through an enhanced induction of cell death, compared with either agent alone; this result was also evident on PC-3R cells. Moreover, we have also demonstrated that apoptosis was induced in prostate cancer cells exposed to these drugs by a concentration-dependent increase in DNA fragmentation and caspase 3/7 enzyme activity. We concluded that ZA, either with docetaxel or not, might still exert some cytotoxicity even in docetaxel-resistant cells. From the clinical perspective, when the clinician decided to change the treatment in the post-docetaxel setting, continuing or combination with ZA may be an effective therapeutic approach for the treatment of HRPC patients.

A cross-sectional survey of the diagnosis and management of bone metastasis in breast cancer patients in Turkey.

PURPOSE: This study aimed to report the practice of managing breast cancer with bone metastasis in Turkey and to determine the adherence to the British Association of Surgical Oncology (BASO) guidelines. METHODS: This multicenter, cross-sectional epidemiological survey was conducted in 38 centers across Turkey. Data from 1,026 breast cancer patients with bone metastases (mean age 54.0 ± 11.9 years) were analyzed. RESULTS: Over 30 % of patients had a diagnosis of metastatic breast cancer (stage IV) at the time of primary diagnosis. The imaging modalities used for diagnosing bone metastases were bone scintigraphy (57.8 %), radiography (22.8 %), and bone survey (4.4 %). Tumor markers were detected in 94.9 %, and markers of bone metabolism were measured in 90.4 % of patients. A total of 3.5 % of patients underwent surgery for bone metastasis, 26.4 % underwent palliative chemotherapy (most commonly docetaxel + capecitabine), and 56.5 % endured radiotherapy. Most patients (96 %) also received bisphosphonate. Radiography, bone scintigraphy, and CT were the main imaging tools used for postoperative follow-up of bone metastasis. Our results were >95 % in line with the BASO guidelines for the management of bone metastasis, except that interventional procedures, such as biopsy, were applied less frequently in our survey. CONCLUSIONS: The diagnosis and management practices of breast cancer with bone metastasis in Turkey were generally compatible with international guidelines. However, the awareness and knowledge of physicians on the current guidelines should be increased, and equipment for the appropriate interventional procedures should be provided in every clinic to obtain optimal and standard management of bone metastases.

Combination of AT-101/cisplatin overcomes chemoresistance by inducing apoptosis and modulating epigenetics in human ovarian cancer cells.

We investigated the effects of AT-101/cisplatin combination treatment on the expression levels of apoptotic proteins and epigenetic events such as DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme activities in OVCAR-3 and MDAH-2774 ovarian cancer cells. XTT cell viability assay was used to evaluate cytotoxicity. For showing apoptosis, both DNA Fragmentation and caspase 3/7 activity measurements were performed. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. DNMT and HDAC activities were evaluated by ELISA assay and mRNA levels of DNMT1 and HDAC1 genes were quantified by qRT-PCR. Combination of AT-101/cisplatin resulted in strong synergistic cytotoxicity and apoptosis in human ovarian cancer cells. Combination treatment reduced some pivotal anti-apoptotic proteins such as Bcl-2, HIF-1A, cIAP-1, XIAP in OVCAR-3 cells, whereas p21, Bcl-2, cIAP-1, HSP27, Clusterin and XIAP in MDAH-2774 cells. Among the pro-apoptotic proteins, Bad, Bax, Fas, phospho-p53 (S46), Cleaved caspase-3, SMAC/Diablo, TNFR1 and Cytochrome c were induced in OVCAR-3 cells, whereas, Bax, TRAILR2, FADD, p27, phospho-p53 (S46), Cleaved caspase-3, Cytochrome c, SMAC/Diablo and TNFR1 were induced in MDAH-2774 cells. Combination treatment also inhibited both DNMT and HDAC activities and also mRNA levels in both ovarian cancer cells. AT-101 exhibits great potential in sensitization of human ovarian cancer cells to cisplatin treatment in vitro, suggesting that the combination of AT-101 with cisplatin may hold great promise for development as a novel chemotherapeutic approach to overcome platinum-resistance in human ovarian cancer.

Efficacy of local ablative therapies in patients with solid tumors treated with immune checkpoint inhibitors and oligoprogression: a single-center analysis.

The concept of oligoprogression reflects a situation where a limited number of metastatic tumor sites have progressed and other metastatic sites are under control with current systemic therapy. The optimal management of oligoprogression remains unclear. In this retrospective study, we evaluated the contribution of local ablative treatment approaches after oligoprogression to progression-free survival and response rates (RRs) in patients with renal cell carcinoma ( N : 5), nonsmall cell lung cancer ( N : 1) and melanoma ( N : 21) who received immunotherapy. We found that patients received local ablative therapies after oligoprogression had longer progression-free survival and higher RR compared to those who did not. Specifically, patients who received concurrent radiotherapy had a median survival time of 24.7 months compared to 14.5 months in those who did not. Our results suggest that local ablative therapies may have a beneficial impact on progression-free survival and RR in patients with oligoprogression who are being treated with immune checkpoint inhibitors. Further studies are needed to confirm these findings and determine the optimal use of local ablative therapies in this setting.

p53 protein accumulation and presence of visceral metastasis are independent prognostic factors for survival in patients with metastatic inflammatory breast carcinoma.

OBJECTIVE: The aim of this study was to determine the markers of prognosis in metastatic inflammatory breast cancer (IBC). SUBJECTS AND METHODS: The prognostic value of patients' clinical characteristics and expression of c-erbB-2, p53, Ki-67, ER and PgR were assessed in the 45 patients with IBC who had developed distant metastasis. Immunohistochemical methods were used to detect the expression of c-erbB-2, p53, Ki-67, ER and PgR in surgical resection specimens of the patients' primary tumor. RESULTS: The median overall survival (OS) measured from the diagnosis of metastatic disease was 23 months. In the univariate analysis, p53 protein accumulation and the presence of visceral metastasis were predictive of poor survival (p = 0.01 and 0.003, respectively). In the multivariate analysis, accumulation of p53 protein and the presence of visceral metastasis correlated with OS (p = 0.02 and 0.008, respectively). CONCLUSION: In metastatic IBC, accumulation of p53 protein and presence of visceral metastasis are independent prognostic factors for OS. Established prognostic factors in non-IBC patients such as patient age, histologic grade, hormone receptor status and c-erbB-2 status did not have independent significance in IBC in this study.

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study.

OBJECTIVES: Regorafenib improved overall survival in patients with metastatic colorectal cancer (mCRC) refractory to standard therapies in two randomised, phase III trials, but has not been evaluated in Turkey. REGARD evaluated the safety and efficacy of regorafenib in Turkish patients with treatment-refractory mCRC. DESIGN: Open-label, single-arm, phase IIIb study conducted between July 2013 and April 2015. SETTING: 11 tertiary centres in Turkey. PARTICIPANTS: Eligible patients were adults with mCRC who had disease progression within 3 months after receiving their last dose of approved standard therapies and who had an Eastern Cooperative Oncology Group performance status ≤1. Patients were excluded if they had previously received regorafenib. Of 139 patients screened, 100 were treated and completed the study, and all 100 were analysed. Fifty-eight per cent were male. INTERVENTIONS: Patients received oral regorafenib, 160 mg once daily, for the first 3 weeks of each 4-week cycle until disease progression, death or unacceptable toxicity. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was safety, assessed by incidence of treatment-emergent adverse events (TEAEs). Progression-free survival (PFS) per investigator was the primary efficacy endpoint. There were no secondary endpoints. RESULTS: The median treatment duration was 2.5 months (range 0.1 to 20.6). Ninety-six per cent of patients had at least one TEAE and 77% had a grade ≥3 TEAE. The most common grade ≥3 regorafenib-related TEAEs were hypophosphataemia (11%), fatigue (8%), hyperbilirubinaemia (6%), hand-foot skin reaction (5%), hypertension (5%), anorexia (5%) and increased alanine aminotransferase (5%). TEAEs led to dose reduction in 30% of patients. Regorafenib-related TEAEs led to treatment discontinuation in 17% of patients. Median PFS was 3.1 months (95% CI 2.9 to 3.8). CONCLUSION: The regorafenib safety profile and PFS in REGARD were consistent with the results of previous trials of regorafenib in mCRC. Regorafenib is an option for patients in Turkey with treatment-refractory mCRC. TRIAL REGISTRATION NUMBER: NCT01853319, ClinicalTrials.gov.

Secondary osteosarcoma arising in fibrous dysplasia, case report.

Malignant transformation of fibrous dysplasia is very rare. The frequency is increased in polyostotic forms, in McCune-Albright and Mazabraud's syndromes and previously irradiated cases. Pain, which is rapidly becoming worse over a short period unrelated to trauma is the most alarming symptom. Early radiological features of sarcomatous transformation are moth-eaten or cystic areas of osteolysis, cortical destruction and gradual formation of a soft tissue mass. The prognosis is unfavorable as most of the cases are in an advanced stage in the time of diagnosis. We present an unusual case of unsuspected secondary osteosarcoma arising in a previously unirradiated, monostotic fibrous dysplasia. A 46-year-old woman was admitted with hip pain, which worsened after a minor trauma occurred 1 year ago. Plain graphies of left femur showed a well-delineated lesion with endosteal scalloping and areas having a ground-glass appearance. The MRI revealed minimal contrast enhancement but no heterogenous signal intensity, cortical destruction, periost reaction or accompanying soft tissue component was noted. The lesion was initially curetted. But being diagnosed as osteosarcoma histologically, classical osteosarcoma protocol pre and postoperative chemotherapy was applied. Resected femur showed areas of fibrous dysplasia admixed with osteosarcoma having fibroblastic, chondroblastic and osteoblastic areas that were focally invading the soft tissue. Tumor viability was estimated as 95%. The clinical course worsened rapidly after the operation. She did not respond to postoperative chemotherapy and lost with pulmonary metastases less than a years' time after the operation. The case is presented to increase awareness on the possibility of malignant transformation in an otherwise unsuspected fibrous dysplasia.

Comparison of inflammatory breast cancer and noninflammatory breast cancer in Western Turkey.

OBJECTIVE: The study was aimed at investigating the clinical and biological features and survival outcomes of patients who were treated for metastatic inflammatory and noninflammatory breast carcinoma. SUBJECTS AND METHODS: One hundred and sixty-seven metastatic breast cancer patients were enrolled into this study and divided into two groups: inflammatory (n = 46) and noninflammatory (n = 121). The clinical and hormone receptor status, c-erbB-2, Ki-67, and p53 expression, based on the immunohistochemical staining patterns, were compared between the two groups. RESULTS: The inflammatory breast carcinoma group had a younger patient population, higher rate of adjuvant anthracycline therapy, number of lymph node metastases, rates of extranodal extension and c-erbB-2 overexpression than noninflammatory breast cancer patients (p < 0.05). With regard to survival, there were slightly better outcomes in the noninflammatory breast carcinoma group (30 months) compared to the inflammatory breast carcinoma group (23 months), but the difference was not statistically significant (p = 0.08). While survival results of p53-negative inflammatory and noninflammatory breast carcinoma patients were similar, p53-positive survival was significantly worse (p < 0.05) in inflammatory breast cancer carcinoma patients. CONCLUSION: Because of c-erbB-2 overexpression in inflammatory breast carcinoma patients, treatment options including trastuzumab could have given better survival outcomes. Survival of inflammatory breast carcinoma patients with a low p53 immunohistochemistry staining appeared similar to that for noninflammatory breast carcinoma. For this reason, new treatment options are needed especially in inflammatory breast carcinoma patients with high p53 positivity.

[A rare cause of catheter-related bacteremia: Rhizobium radiobacter]. / Nadir bir katetere bagli bakteriyemi etkeni: Rhizobium radiobacter.

Rhizobium spp. (R. radiobacter, R. rhizogenes, R. rubi, R. vitis) are aerobic, motile, non-spore forming, oxidase-positive, gram-negative bacilli. Although they are mostly plant pathogens, R. radiobacter may cause human infections. The aim of this report was to present a case of R. radiobacter bacteremia treated with levofloxacin. Twenty-seven year old male patient had fever after receiving chemotherapy due to osteosarcoma. The infection focus could not be detected in the initial physical examination. Blood cultures were obtained from peripheral veins and central catheter and levofloxacin (500 mg/day) was started as empirical therapy. His fever resolved on the next day. Meanwhile cultures of blood (Bact/Alert automated systems, bioMerieux, Durham, NC) obtained from peripheral veins and central catheters yielded bacteria which were identified as R. radiobacter by VITEK 2 (bioMerieux Inc, Mercy L'etoil, France). The strain was resistant to amikacin and sensitive to ceftazidime, ciprofloxacin, imipenem, meropenem and piperacillin/tazobactam. The patient was diagnosed as catheter-related bacteremia and the treatment was continued for 14 days. His catheter was not removed since subsequent cultures did not reveal any bacterial growth. In conclusion this case suggests that R. radiobacter may cause infections especially in immunocompromised patients with catheters or prosthetic devices. To our knowledge this is the first R. radiobacter case reported from Turkey and the first case of R. radiobacter bacteremia reported to be treated with levofloxacin in the literature.

Ovarian sertoli-leydig cell tumors: A multicenter long-term clinicopathological analysis of 27 patients.

AIM: Information on the clinical behavior of ovarian Sertoli-Leydig cell tumors (SLCTs) as well as its prognostic factors and optimal management is limited due to a substantially low incidence of the disease. Also, limited data is available regarding the role of chemotherapy in the management of SLCTs. The aim of the study is to evaluate clinicopathological features and outcome of patients with ovarian SLCTs. MATERIALS AND METHODS: Twenty-seven patients with SLCT treated at two centers were reviewed retrospectively during 21 years. RESULTS: The median age was 45 years (range, 16-81) and the mean follow-up time was 86 months (range, 16-181). Twenty-three patients had stage IA, three patients had IC, and one patient had stage II disease. Eleven tumors (41%) were well-differentiated and 16 (59%) tumors were intermediately differentiated. Nine patients underwent unilateral salpino-oophorectomy and one patient, with a history of infertility, underwent cystectomy for fertility preservation. Eight patients with intermediately differentiated types of SLCT received adjuvant systemic chemotherapy including the combination bleomycin, etoposide, and cisplatin (BEP). Recurrence occurred in one patient with intermediated differentiated type SLCT with heterologous elements. She received four cycles of BEP chemotherapy. Twelve months later, she underwent cytoreductive surgery and received six cycles of cisplatin plus carboplatin. She died 24 months after the initial diagnosis. CONCLUSION: SLCTs of the ovary are usually in early stage, unilateral, and benign. Fertility-sparing surgery is the preferred option in young women. In the adjuvant treatment setting, although information about chemotherapy is limited, BEP is a commonly used regimen. The degree of differentiation and the presence of heterologous elements relate to a poor prognosis.

The retrospective analysis of patients with uterine sarcomas: A single-center experience.

BACKGROUND: Uterine sarcomas are rare, malignant, gynecological tumors and show diverse histopathological features. Therefore, there is no consensus on risk factors for poor outcome and optimal treatment. The aim of this retrospective analysis is to report the clinical outcome of patients with uterine sarcoma treated at a single center. MATERIALS AND METHODS: The data was obtained regarding the patient's demographic characteristics, pathological results, treatments given, survival, and complications of all uterine sarcoma patients treated in a single center between the years 2000 and 2012. The 80.month overall survival. (OS) was determined with respect to prognostic factors including age, stage of disease, histopathological type, and adjuvant treatment. RESULTS: A total of 57 case records are retrieved for this retrospective analysis. The mean age of the patients is 62.5 ± 11.2 years. International Federation of Gynecology and Obstetrics (FIGO) stage distribution is stage I: 29; stage II: 13; stage III: 9; stage IV: 6. Fifty-seven patients underwent surgery, 33 received postoperative radiotherapy (PORT), and 32 received chemotherapy. Median follow-up period was 25 months (range 2-85 months). The 80-month OS for the entire group of patients was 36.7%. The significant prognostic factors for survival are age under 50 years, stage of disease, and adjuvant chemotherapy. CONCLUSION: Although limited by small sample size and retrospective nature, age under 50 years, stage of disease, and adjuvant chemotherapy are significant prognostic factors for survival for uterine sarcomas.

Capecitabine maintenance therapy following docetaxel/capecitabine combination treatment in patients with metastatic breast cancer.

The present study aimed to analyze the efficacy of maintenance therapy with single agent capecitabine for human epidermal growth factor receptor (HER2) negative metastatic breast cancer (MBC) patients following disease control with 6 cycles of docetaxel plus capecitabine chemotherapy as the first-line treatment. As an initial treatment, 6 cycles of docetaxel plus capecitabine followed by maintenance therapy with capecitabine were administered. A total of 55 patients received combination therapy and 48 patients proceeded to maintenance therapy: Of these, 32 patients (66.7%) were postmenopausal and 37 (77.1%) had estrogen and progesterone receptor positive disease. The median progression-free survival rate with maintenance therapy was 5.5 months (95% CI, 0-11.4 months) and the median overall survival (OS) was 26.6 months (95% CI, 21.8-30.1 months). The use of maintenance therapy improved previous responses in 4 patients (8.3%; 2 partial and 2 complete responses) and 32 patients (66.7%) had stable disease. The median number of maintenance therapy cycles applied was 6.5 (range 1-28, total 441). The observation of side effects, including grade 3/4 neutropenia, febrile neutropenia and fatigue was more common during combination therapy. The results of the present study indicate that maintenance with single agent capecitabine therapy is an effective and tolerable treatment option for HER2 negative MBC patients in which disease control with 6 cycles of docetaxel plus capecitabine chemotherapy is achieved in the first-line setting.

Docetaxel in combination with octreotide shows synergistic apoptotic effect by increasing SSTR2 and SSTR5 expression levels in prostate and breast cancer cell lines.

PURPOSE: Docetaxel (DTX) is widely used for the treatment of metastatic prostate and breast cancers. Despite the clinical success of DTX, drug-related cumulative toxicity restricts its clinical use in cancer therapy. Thus, there is an urgent need for new therapeutic options. Octreotide (OCT) is a synthetic somatostatin analog that induces apoptosis in different cancer cell lines in vitro. In this study, we investigated the possible synergistic apoptotic effects of DTX in combination with OCT in prostate and breast cancer cell lines. METHODS: The XTT cell viability assay was used to determine cytotoxicity. Apoptosis was evaluated by Cell Death Detection ELISA(Plus) Kit. The expression levels of apoptotic proteins were assessed by human apoptosis antibody array. Levels of SSTR2 and SSTR5 proteins were determined by western blot analysis. RESULTS: DTX and OCT combination induced apoptosis in both breast and prostate cancer cells in a concentration- and time-dependent manner. Moreover, combination treatment resulted in inhibition of anti-apoptotic proteins such as Bcl-2 and Bcl-xL and induction of pro-apoptotic proteins Bax, Cytochrome c and IAPs in all of the tested cancer cell lines. SSTR2 and SSTR5 protein levels were induced as compared to any agent alone. CONCLUSIONS: These results indicate that this combination treatment is a significant inducer of apoptosis in a synergistic manner in breast and prostate cancer cells. This strong synergism helps to lower the dose of DTX in both types of cancers, thus letting DTX to be used for longer periods by delaying resistance development and lesser side effects.

Arsenic trioxide and methylprednisolone use different signal transduction pathways in leukemic differentiation.

Certain cell lines like HL 60 and K 562 are utilised as leukemic cell models for leukemogenesis research, which differentiate along the granulocytic and/or monocytic pathway when treated with certain inducer molecules. High dose methylprednisolone treatment has been shown to induce in vivo and in vitro differentiation of myeloid leukemia cells to mature granulocytes in patients with acute promyelocytic leukemia (APL) and other subtypes of acute myeloid leukemia (AML). Arsenic trioxide (As(2)O(3)) has been confirmed to have remission induction effects on APL. However, there are conflicting results on the effects with other AML subtypes. Also, it has been well established that the reversible phosphorylation of proteins is a major regulatory mechanism in the signal transduction pathways that control cell growth and differentiation. Serine/threonine protein phosphatases (PP) are major components of phosphorylation. In this study, we investigated the effect of As(2)O(3) on HL 60 and K 562 myeloid leukemic differentiation and compared the signalling cascades of the two inducers with respect to serine/threonine PP 1 and 2A. We utilised PP1 and PP2A inhibitors okadaic acid and calyculin A. In contrast to methylprednisolone, there was no effect of phosphatase inhibitors on As(2)O(3)-induced leukemic differentiation. Incomplete leukemic differentiation occurred with lower As(2)O(3) concentration as 10(-6)M. Unlike As(2)O(3), methylprednisolone induced complete granulocytic and/or monocytic differentiation of HL 60 and K 562 cells via upregulation of PP2A regulatory subunits. Therefore, As(2)O(3) and methylprednisolone are promising agents that have the potential to be used together in myeloid leukemic differentiation therapy.

Differential effects of doxorubicin and docetaxel on nitric oxide production and inducible nitric oxide synthase expression in MCF-7 human breast cancer cells.

Anthracyclines and docetaxel are frequently used agents in the chemotherapy of breast cancer. In this study we examined the role of inducible nitric oxide synthase (iNOS) expression during the cytotoxicity of these drugs in the MCF-7 breast cancer cell line. Cell viability and cytotoxicity were evaluated by the trypan blue dye exclusion method. Apoptosis and necrosis were determined by the acridine orange/ethidium bromide dye method. The percentage of apoptotic cells was significantly higher with doxorubicin. However, total cytotoxic cell numbers were higher in the docetaxel group compared with doxorubicin, with respect to the control. Most of the cells were seen to be necrotic with the dye method. Cell extracts during the apoptotic process were applied to immunoblot by anti-iNOS monoclonal antibodies. While there was an increase in iNOS expression during docetaxel induced-cytotoxicity, a significant decrease in iNOS expression was detected during doxorubicin-induced cytotoxicity. The Griess method was used for detection of nitrate levels. It was compatible with immunoblot results. These data open a window for further studies to understand the mechanism underlining the cytotoxicity of docetaxel and doxorubicin.

Alterations in the activity and expression of serine/threonine protein phosphatases during all trans retinoic acid-induced apoptosis in breast cancer cells.

Retinoids exert different effects on malignant cells with various phenomena. They can induce differentiation and apoptosis in various cancer cells. However, the underlying mechanism of these effects is not clear. There are data related to the role of protein phosphatases during retinoid-induced leukemic cell differentiation. The aim of this study was to evaluate effects of the All trans retinoic acid (ATRA) on protein/serine phosphatases during ATRA induced apoptosis in the breast cancer cells. The MTT assay was used to determine drug-mediated cytotoxicity. A cell death detection ELISA kit was used for detection of the DNA fragments. The activity of serine/threonine protein phosphatases was assayed by the serine/threonine phosphatase system. The expression of serine/threonine protein phosphatases was evaluated by Western blot. During ATRA treatment, a significant decrease in the activity of serine/threonine phosphatases 2A, B and C occurred. The decreased activity of PP2A correlated with the up-regulation of PP2A catalytic and PP2A/B gamma, PP2A/B alpha regulatory subunits. The decrease in activity of the PP2B correlated with down-regulation of PP2B catalytic and up-regulation of PP2B regulatory subunit expression. In addition, there was an up-regulation in PP4C and down regulation in PP2C alpha/beta subunits protein expression. We demonstrated clear alteration in the activity and expression of serine/threonine protein phosphatases in breast cancer cells during ATRA treatment, and we suggest that the ATRA-induced apoptosis of the MCF-7 cells is significantly related to the phosphorylation dynamics.