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Web Resources: Teniposide
Recent Research Publications

Web Resources: Teniposide (4 links)

Recent Research Publications

Singapore Cancer Network (SCAN) Guidelines for Systemic Therapy of High-Grade Glioma.
Ann Acad Med Singapore. 2015; 44(10):463-73 [PubMed] Related Publications
INTRODUCTION: The SCAN Neuro-Oncology workgroup aimed to develop Singapore Cancer Network (SCAN) clinical practice guidelines for systemic therapy for high-grade glioma in Singapore.
MATERIALS AND METHODS: The workgroup utilised a modified ADAPTE process to calibrate high quality international evidence-based clinical practice guidelines to our local setting.
RESULTS: Six international guidelines were evaluated- those developed by the National Comprehensive Cancer Network (2013), the European Association for Neuro-Oncology (EANO) Task Force on Malignant Glioma (2014), the European Society of Medical Oncology (2014), the Canadian GBM Recommendations Committee (2007) and the Australian Cancer Network (2009). Recommendations on the systemic therapy of high-grade glioma were produced.
CONCLUSION: These adapted guidelines form the SCAN Guidelines 2015 for systemic therapy of high-grade glioma.

Nascimento FA, Nery J, Trennepohl J, Pianovski MA
Hemophagocytic Lymphohistiocytosis After Initiation of Chemotherapy for Bilateral Adrenal Neuroblastoma.
J Pediatr Hematol Oncol. 2016; 38(1):e13-5 [PubMed] Related Publications
Hemophagocytic lymphohistiocytosis (HLH) is a rare and aggressive syndrome characterized by overactivation of the immune system. Although secondary HLH has been frequently associated with malignancies, this entity is rarely triggered by solid tumors, such as neuroblastomas. Herein, we describe a 14-month-old girl with a late diagnosis of bilateral adrenal neuroblastoma who developed HLH 6 days after the initiation of chemotherapy. On the basis of the large tumoral mass and the time of onset of her symptoms suggestive of HLH, we hypothesize that tumor cell destruction induced by chemotherapy drugs was the trigger to the development of hematophagocytic lymphohistiocytosis syndrome.

Hobeika L, Self SE, Velez JC
Renal thrombotic microangiopathy and podocytopathy associated with the use of carfilzomib in a patient with multiple myeloma.
BMC Nephrol. 2014; 15:156 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Proteasome inhibitors are a relatively new class of chemotherapeutic agents. Bortezomib is the first agent of this class and is currently being used for the treatment of multiple myeloma. However, recent reports have linked exposure to bortezomib with the development of thrombotic microangiopathy. A new agent in this class, carfilzomib, has been recently introduced as alternative therapy for relapsing and refractory multiple myeloma. We report a case of renal thrombotic microangiopathy associated with the use of carfilzomib in a patient with refractory multiple myeloma.
CASE PRESENTATION: A 62 year-old Caucasian man with hypertension and a 4-year history of multiple myeloma, had been previously treated with lenalidomide, bortezomib and two autologous hematopoietic stem cell transplants. After the second hematopoietic stem cell transplant, he developed acute kidney injury secondary to septic shock and required dialysis for 4 weeks. Subsequently, his serum creatinine stabilized at 2.1 mg/dL (185.64 μmol/L). Seventeen months after the second hematopoietic stem cell transplant, he was initiated on carfilzomib for relapse of multiple myeloma. Six weeks later, he developed abrupt worsening of lower extremity edema and hypertension, and new onset proteinuria. His kidney function remained stable. Kidney biopsy findings were consistent with thrombotic microangiopathy. Eight weeks after discontinuation of carfilzomib, proteinuria and hypertension improved. Due to progression of multiple myeloma, he died a few months later.
CONCLUSION: In view of the previously reported association of bortezomib with thrombotic microangiopathy, the temporal association of the clinical picture with the initiation of carfilzomib, and the partial resolution of symptoms after discontinuation of the drug, we conclude that carfilzomib may have precipitated a case of clinically evident renal thrombotic microangiopathy in our patient.

Sun YC, Wang J, Guo CC, et al.
MiR-181b sensitizes glioma cells to teniposide by targeting MDM2.
BMC Cancer. 2014; 14:611 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Although the incidence of glioma is relatively low, it is the most malignant tumor of the central nervous system. The prognosis of high-grade glioma patient is very poor due to the difficulties in complete resection and resistance to radio-/chemotherapy. Therefore, it is worth investigating the molecular mechanisms involved in glioma drug resistance. MicroRNAs have been found to play important roles in tumor progression and drug resistance. Our previous work showed that miR-181b is involved in the regulation of temozolomide resistance. In the current study, we investigated whether miR-181b also plays a role in antagonizing the effect of teniposide.
METHODS: MiR-181b expression was measured in 90 glioma patient tissues and its relationship to prognosis of these patients was analyzed. Cell sensitivity to teniposide was tested in 48 primary cultured glioma samples. Then miR-181b stably overexpressed U87 cells were generated. The candidate genes of miR-181b from our previous study were reanalyzed, and the interaction between miR-181b and target gene MDM2 was confirmed by dual luciferase assay. Cell sensitivity to teniposide was detected on miR-181b over expressed and MDM2 down regulated cells.
RESULTS: Our data confirmed the low expression levels of miR-181b in high-grade glioma tissues, which is related to teniposide resistance in primary cultured glioma cells. Overexpression of miR-181b increased glioma cell sensitivity to teniposide. Through target gene prediction, we found that MDM2 is a candidate target of miR-181b. MDM2 knockdown mimicked the sensitization effect of miR-181b. Further study revealed that miR-181b binds to the 3'-UTR region of MDM2 leading to the decrease in MDM2 levels and subsequent increase in teniposide sensitivity. Partial restoration of MDM2 attenuated the sensitivity enhancement by miR-181b.
CONCLUSIONS: MiR-181b is an important positive regulator on glioma cell sensitivity to teniposide. It confers glioma cell sensitivity to teniposide through binding to the 3'-UTR region of MDM2 leading to its reduced expression. Our findings not only reveal the novel mechanism involved in teniposide resistance, but also shed light on the optimization of glioma treatment in the future.

Ahmad AK, Hui P, Litkouhi B, et al.
Institutional review of primary non-hodgkin lymphoma of the female genital tract: a 33-year experience.
Int J Gynecol Cancer. 2014; 24(7):1250-5 [PubMed] Related Publications
OBJECTIVE: The aim of this is to provide an updated review of the literature and to report our institutional experience with this rare gynecologic malignancy.
METHODS: The medical records of patients with diagnosis of non-Hodgkin lymphoma of the female genital tract from 1980 to 2013 at the Yale-New Haven Hospital were reviewed retrospectively. Histological classification and staging were determined by the World Health Organization and Ann Arbor systems, respectively. Kaplan-Meier was used to calculate the survival.
RESULTS: There were 36 patients with diagnosis of non-Hodgkin lymphoma of the female genital tract and followed for a median of 61 months (0-361 months). The median age of diagnosis was 44 years (19-87 years), and 76% (n = 28) were classified as stage IV.Of these, 4 patients were asymptomatic on presentation, and 13 were identified incidentally during surgery/radiography (n = 9), on prenatal ultrasound (n = 1), and on Papanicolaou test (n = 3). The location of the disease included the ovary (n = 6), uterine corpus and cervix (n= 9), vagina (n = 1), a pelvic mass (n = 7), isolated pelvic/para-aortic lymph nodes (n = 3), and/or multiple sites (n = 9). There were 6 cases that were concomitant with other gynecologic malignancies.Diffuse large B-cell lymphoma (n= 18) was the most common histologic type. A total of 28 patients underwent surgery. Combination chemotherapy was used in 34 patients, with concomitant radiation therapy in 7 and stem cell transplantation in 3. A total of 5 patients had recurrent disease.The overall median survival from the diagnosis of lymphoma was 70 months (0.3-361 months) with a 91% 1-year survival, 86% 5-year survival, and a 79% 10-year survival.
CONCLUSIONS: Our report is the largest published single-institution experience of this disease. It demonstrates a more favorable prognosis and proposes that with early diagnosis and appropriate therapy, radical gynecologic surgery can be avoided.

Wu JJ, Wang XH, Li L, et al.
Fotemustine, teniposide and dexamethasone in treating patients with CNS lymphoma.
Asian Pac J Cancer Prev. 2014; 15(11):4733-8 [PubMed] Related Publications
PURPOSE: We developed and evaluated a regimen including fotemustine, teniposide and dexamethasone (FTD) for treating patients with central nervous system (CNS) lymphoma based on pharmacokinetic properties of individual agents and in combination.
PATIENTS AND METHODS: In a comparison study, 8 patients with primary CNS lymphoma (PCNSL) and 8 with secondary CNS lymphoma (SCNSL) were treated with FTD (comprising fotemustine 100 mg/m2, 1h infusion, day 1; teniposide 60 mg/m2, >0.5 h infusion, on day 2, 3, 4; dexamethasone 40 mg, 1h infusion, on day 1, 2, 3, 4 and 5; and methotrexate 12 mg, cytosine arabinoside 50 mg plus dexamethasone 5 mg intrathecally, on day 2 and 7). Cycles were repeated every 3 weeks. After response assessment, patients received whole brain radiotherapy.
RESULTS: Of the 8 PCNSL patients, 4 (50%) achieved CR and 3 (38%) PR, an overall response rate of 88%. Four patients (50%) were in continuing remission at the end of this study after a median follow-up of 30 months (range 10 to 56 months). Of the 8 SCNSL patients the overall response rate was 63% (CR+PR:38%+25%). All responses were achievable with predictable toxicity mainly reflecting reversible myelosuppression.
CONCLUSION: This study suggests that FTD could be an effective treatment for CNS lymphoma, and is worthy of further evaluation.

Mack F, Schäfer N, Kebir S, et al.
Carmustine (BCNU) plus Teniposide (VM26) in recurrent malignant glioma.
Oncology. 2014; 86(5-6):369-72 [PubMed] Related Publications
BACKGROUND: After the failure of radiotherapy and temozolomide, there is no established standard therapy for patients with recurrent glioblastoma (GBM). Based on the promising data of a previous trial (NOA-01) for primary GBM and some retrospective case series for GBM recurrence, the combination of nimustine and teniposide (VM26) was commonly used in this setting. When nimustine was no longer available in Europe, we switched to intrvaveneous carmustine (BCNU). Data on the toxicity and efficacy of BCNU and VM26 in recurrent GBM are lacking.
METHODS: In our neurooncological center, all patients with recurrent GBM or with progressed glioma and a typical MRI lesion suggesting GBM treated with BCNU (130-150 mg/m(2), day 1/42) and VM26 (45-60 mg/m(2), days 1-3/42) were analyzed retrospectively for progression-free survival, overall survival and toxicity.
RESULTS: Fifteen patients (median age 52 years) were identified. Median progression-free survival was 2 months and median overall survival was 4 months. Two patients (14%) developed grade 3/4 hematotoxicity. Nonhematological toxicity ≥grade 3 was not observed.
CONCLUSION: Our data do not support the application of BCNU/VM26 in patients with late stages of recurrent GBM.

Li WQ, Yu HY, Li YM, et al.
Higher LRRFIP1 expression in glioblastoma multiforme is associated with better response to teniposide, a type II topoisomerase inhibitor.
Biochem Biophys Res Commun. 2014; 446(4):1261-7 [PubMed] Related Publications
Previous studies from this laboratory indicated that microRNA-21 (miR-21) contributes to chemoresistance of glioblastoma multiforme (GBM) cells to teniposide, a type II topoisomerase inhibitor. We also showed that LRRFIP1 is a target of miR-21. In this study, we found that higher baseline LRRFIP1 expression in human GBM tissue (n=60) is associated with better prognosis upon later treatment with teniposide. Experiments in cultured U373MG cells showed enhanced toxicity of teniposide against U373MG cells transfected with a vector that resulted in LRRFIP1 overexpression (vs. cells transfected with control vector). Experiments in nude mice demonstrated better response of LRRFIP1 overexpressing xenografts to teniposide. These findings indicate that high baseline LRRFIP1 expression in GBM is associated with better response to teniposide, and encourage exploring LRRFIP1 as a target for GBM treatment.

Thiepold AL, Lemercier S, Franz K, et al.
Prophylactic use of pegfilgrastim in patients treated with a nitrosourea and teniposide for recurrent glioma.
Pharmacotherapy. 2014; 34(6):633-42 [PubMed] Related Publications
STUDY OBJECTIVE: As chemotherapy with teniposide and a nitrosourea is commonly used for the treatment of patients with recurrent glioma but can be associated with severe myelotoxicity, we sought to determine if prophylactic administration of pegfilgrastim could reduce leukopenia or infectious complications in patients receiving this chemotherapeutic regimen.
DESIGN: Retrospective medical record review.
SETTING: University-affiliated neurooncology hospital in Frankfurt, Germany.
PATIENTS: Sixty-four patients who received at least one cycle of a nitrosourea agent (nimustine or lomustine) and teniposide for recurrent glioma between 2008 and 2012; of these patients, 28 did not receive prophylactic pegfilgrastim (cohort A), and 36 patients received prophylactic pegfilgrastim (cohort B).
MEASUREMENTS AND MAIN RESULTS: Blood counts, hospitalizations due to infection or myelosuppression, use of intravenous antibiotics, and survival parameters were analyzed. Leukopenia was more frequently observed before day 30 (early nadir) versus from 30 days until the next cycle (late nadir). In cohort B, Common Terminology Criteria for Adverse Events grade 3 leukopenia in the early nadir occurred less often compared with cohort A (9% in cohort B vs 31% in cohort A). However, the frequency of grade 4 leukopenia, number of days in the hospital due to infection or myelosuppression, days on intravenous antibiotics, progression-free survival, and overall survival were similar between the cohorts.
CONCLUSION: Moderate, but not severe, leukopenia or related complications could be prevented by prophylactic pegfilgrastim in patients treated with a nitrosourea and teniposide for recurrent glioma. Our results, therefore, do not support routine prophylactic use of pegfilgrastim in these patients.

Tower RL, Jones TL, Camitta BM, et al.
Dose intensification of methotrexate and cytarabine during intensified continuation chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: POG 9406: a report from the Children's Oncology Group.
J Pediatr Hematol Oncol. 2014; 36(5):353-61 [PubMed] Free Access to Full Article Related Publications
PURPOSE: To determine the efficacy and toxicity of higher dose versus standard dose intravenous methotrexate (MTX) and pulses of high-dose cytosine arabinoside with asparaginase versus standard dose cytosine arabinoside and teniposide during intensified continuation therapy for higher risk pediatric B-precursor acute lymphoblastic leukemia (ALL).
PATIENTS AND METHODS: From 1994 to 1999, the Pediatric Oncology Group conducted a randomized phase III clinical trial in higher risk pediatric B-precursor ALL. A total of 784 patients were randomized in a 2×2 factorial design to receive MTX 1 g/m versus 2.5 g/m and to cytosine arabinoside/teniposide versus high-dose cytosine arabinoside/asparaginase during intensified continuation therapy.
RESULTS: Patients receiving standard dose MTX had a 5-year disease-free survival (DFS) of 71.8±2.4%; patients receiving higher dose MTX had a 5-year DFS of 71.7±2.4% (P=0.55). Outcomes on cytosine arabinoside/teniposide (DFS of 70.4±2.4) were similar to higher dose cytosine arabinoside/asparaginase (DFS of 73.1±2.3%) (P=0.41). Overall survival rates were not different between MTX doses or cytosine arabinoside/teniposide versus cytosine arabinoside/asparaginase.
CONCLUSIONS: Increasing MTX dosing to 2.5 g/m did not improve outcomes in higher risk pediatric B-precursor ALL. Giving high-dose cytarabine and asparaginase pulses instead of standard dose cytarabine and teniposide produced nonsignificant differences in outcomes, allowing for teniposide to be removed from ALL therapy.

Sullivan EM, Wilson MW, Billups CA, et al.
Pathologic risk-based adjuvant chemotherapy for unilateral retinoblastoma following enucleation.
J Pediatr Hematol Oncol. 2014; 36(6):e335-40 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: There are no standardized diagnostic or treatment guidelines for patients with advanced unilateral retinoblastoma.
MATERIALS AND METHODS: Patients with advanced unilateral retinoblastoma were prospectively treated after enucleation using a risk-based protocol. Patients were assigned to low risk (LR), intermediate risk (IR), or high risk (HR) based on pathology. LR patients underwent observation. IR patients received 4 courses of chemotherapy with vincristine, doxorubicin, and cyclophosphamide (VDC). In the HR group, patients received 3 courses of VDC alternating with 3 courses of vincristine, carboplatin, and etoposide (VCE) and irradiation when indicated.
RESULTS: Fifty patients with advanced unilateral retinoblastoma were treated (LR, n=36; IR, n=7; HR, n=7). All eyes were Reese-Ellsworth group V. All bone scans (n=81), lumbar punctures (n=16), and bone marrow aspirates (n=16) were negative. Chemotherapy was well tolerated. Grades 3/4 hematologic toxicities were seen in all patients; grades 3/4 nonhematologic toxicities were seen in half the patients. Only one patient in the HR group received radiation therapy. All patients were alive at the time of analysis with no signs of disease recurrence. Median follow-up was 3.4 years (range, 0.8 to 6.4 y).
CONCLUSIONS: Patients with nonmetastatic unilateral retinoblastoma undergoing primary enucleation can be cured with a graduated intensity approach based on pathology.

Kortuem KM, Zidich K, Schuster SR, et al.
Activity of 129 single-agent drugs in 228 phase I and II clinical trials in multiple myeloma.
Clin Lymphoma Myeloma Leuk. 2014; 14(4):284-290.e5 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: More than 400 preclinical studies report ≥ 1 compound as cytotoxic to multiple myeloma (MM) cells; however, few of these agents became relevant in the clinic. Thus, the utility of such assays in predicting future clinical value is debatable.
PATIENTS AND METHODS: We examined the application of early-phase trial experiences to predict future clinical adoption. We identified 129 drugs explored as single agents in 228 trials involving 7421 patients between 1961 and 2013.
RESULTS: All drugs in common use in MM (melphalan, dexamethasone, prednisone, cyclophosphamide, bendamustine, thalidomide, lenalidomide, pomalidomide, bortezomib, carfilzomib, and doxorubicin) demonstrated a best reported response rate of ≥ 22%. Older agents, including teniposide, fotemustine, paclitaxel, and interferon, also appear active by this criterion; however, if mean response rates from all reported trials for an agent are considered, then only drugs with a mean response rate of 15% partial response are in clinical use.
CONCLUSION: Our analysis suggests that thresholds of 20% for best or 15% for mean response are highly predictive of future clinical success. Below these thresholds, no drug has yet reached regulatory approval or widespread use in the clinic. Thus, this benchmark provides 1 element of the framework for guiding choice of drugs for late-stage clinical testing.

Linz U, Ulus B, Neuloh G, et al.
Can in-vitro chemoresponse assays help find new treatment regimens for malignant gliomas?
Anticancer Drugs. 2014; 25(4):375-84 [PubMed] Related Publications
Various in-vitro chemosensitivity and resistance assays (CSRAs) have been demonstrated to be helpful decision aids for non-neurological tumors. Here, we evaluated the performance characteristics of two CSRAs for glioblastoma (GB) cells. The chemoresponse of fresh GB cells from 30 patients was studied in vitro using the ATP tumor chemoresponse assay and the chemotherapy resistance assay (CTR-Test). Both assay platforms provided comparable results. Of seven different chemotherapeutic drugs and drug combinations tested in vitro, treosulfan plus cytarabine (TARA) was the most effective, followed by nimustine (ACNU) plus teniposide (VM26) and temozolomide (TMZ). Whereas ACNU/VM26 and TMZ have proven their clinical value for malignant gliomas in large randomized studies, TARA has not been successful in newly diagnosed gliomas. This seeming discrepancy between in vitro and clinical result might be explained by the pharmacological behavior of treosulfan. Our results show reasonable agreement between two cell-based CSRAs. They appear to confirm the clinical effectiveness of drugs used in GB treatment as long as pharmacological preconditions such as overcoming the blood-brain barrier are properly considered.

Wang Y, Chen X, Zhang Z, et al.
Comparison of the clinical efficacy of temozolomide (TMZ) versus nimustine (ACNU)-based chemotherapy in newly diagnosed glioblastoma.
Neurosurg Rev. 2014; 37(1):73-8 [PubMed] Related Publications
Although temozolomide (TMZ) replaced nitrosoureas as the standard initial chemotherapy for glioblastoma (GBM), no studies have compared TMZ with nimustine (ACNU), a nitrosourea agent widely used in central Europe and most Asian regions. One hundred thirty-five patients with GBM who underwent extensive tumor resection in our institution received both radiation and chemotherapy as initial treatment, 34 received TMZ and 101 ACNU-based (ACNU plus teniposide or cisplatin) chemotherapy. Efficacy analysis included overall survival (OS) and progression-free survival (PFS). The following prognostic factors were taken into account: age, performance status, extent of resection, and O(6)-methylguanine-DNA-methyltransferase (MGMT) gene status. The median OS was superior in the TMZ versus the ACNU group (p = 0.011), although MGMT gene silencing, which is associated with a striking survival benefit from alkylating agents, was more frequent in the ACNU group. In multivariate Cox analysis adjusting for the common prognostic factors, TMZ chemotherapy independently predicted a favorable outcome (p = 0.002 for OS, hazard ratio [HR], 0.45; p = 0.011 for PFS, HR, 0.56). Given that >40 % of patients in ACNU group did not receive the intensive chemotherapy cycles because of severe hematological and nonhematological toxicity, we performed a further subanalysis for patients who received at least 4 cycles of chemotherapy. Although a modest improvement in survival occurred in this ACNU subgroup, the efficacy was still inferior to that in the TMZ cohort. Our data suggest that the survival benefit of TMZ therapy is superior to that of an ACNU-based regimen in patients with extensive tumor resection, also shows greater tolerability.

Leonard A, Wolff JE
Etoposide improves survival in high-grade glioma: a meta-analysis.
Anticancer Res. 2013; 33(8):3307-15 [PubMed] Related Publications
BACKGROUND: The purpose of this meta-analysis was to evaluate the therapeutic efficacy of topoisomerase inhibitors in the treatment of high-grade gliomas (HGGs).
MATERIALS AND METHODS: Using median overall survival (mOS) and survival gain, we compared the efficacy of chemotherapy drugs in a meta-analysis of 624 HGG studies, including 44,850 patients from studies published between 1976 and 2011.
RESULTS: Patient cohorts treated with etoposide had significant improvement in mOS (15.66 months vs. 13.27 months, p=0.026, 49 vs. 795 cohorts) and significant survival gain advantage (p=0.022) over cohorts treated without etoposide. In contrast, patient cohorts treated with irinotecan had significantly worse mOS (10.20 vs. 13.55 months, p=0.008, 35 vs. 810 cohorts) and a disadvantage compared to cohorts treated without irinotecan in survival gain analysis.
CONCLUSION: Results from this analysis suggest that etoposide may improve overall survival for patients with HGG, whereas the use of irinotecan might result in inferior outcomes.

Zhao XC, Dou GR, Wang L, et al.
Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells.
Neoplasia. 2013; 15(7):815-25 [PubMed] Free Access to Full Article Related Publications
The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2(+) perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

Zhang Z, Liu Z, Ma L, et al.
Reversal of multidrug resistance by mitochondrial targeted self-assembled nanocarrier based on stearylamine.
Mol Pharm. 2013; 10(6):2426-34 [PubMed] Related Publications
Multidrug resistance (MDR) remains one of the major challenges for successful chemotherapy. Herein, we tried to develope a mitochondria targeted teniposide loaded self-assembled nanocarrier based on stearylamine (SA-TSN) to reverse MDR of breast cancer. SA-TSN was nanometer-sized spherical particles (31.59 ± 3.43 nm) with a high encapsulation efficiency (99.25 ± 0.21%). The MDR in MCF-7/ADR cells was obviously reduced by SA-TSN, which mainly attributed to the markedly reduced expression of P-gp, increased percentages in G2 phase, selectively accumulation in mitochondria, decrease of mitochondrial membrane potential, and greatly improved apoptosis. The plasma concentration of teniposide was greatly improved by SA-TSN, and the intravenously administered SA-TSN could accumulate in the tumor site and penetrate into the inner site of tumor in MCF-7/ADR induced xenografts. In particular, the in vivo tumor inhibitory efficacy of SA-TSN in MCF-7/ADR induced models was more effective than that of teniposide loaded self-assembled nanocarrier without stearylamine (TSN) and teniposide solution (TS), which verified the effectiveness of SA-TSN in reversal of MDR. Thereby, SA-TSN has potential to circumvent the MDR for the chemotherapy of breast cancer.

Bachy E, Houot R, Morschhauser F, et al.
Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma.
Haematologica. 2013; 98(7):1107-14 [PubMed] Free Access to Full Article Related Publications
Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity.

Huang D, Zhang Y, Zhang W, et al.
Study on clinical therapeutic effect including symptoms, eye preservation rate, and follow-up of 684 children with retinoblastoma.
Eur J Ophthalmol. 2013 Jul-Aug; 23(4):532-8 [PubMed] Related Publications
INTRODUCTION: Retinoblastoma is the most common type of primary malignant intraocular tumor in children. The purpose of this study is to summarize the clinical experience of diagnosis and treatment for retinoblastoma, aiming to provide appropriate knowledge for surveillance and therapy for retinoblastoma.
METHODS: We performed retrospective analysis of 684 children (885 eyes) with advanced retinoblastoma diagnosed in the department of Pediatrics in Tongren Hospital, Beijing, China, between September 2005 and May 2010.
RESULTS: The average age at first diagnosis was 2.2 ± 1.7 years with overall median age 1.91 years. Leucocoria was the most common sign at the initial diagnosis (70.47%, 482/684). A total of 21 cases (3.06%) had positive family history. According to International Retinoblastoma Classification, 551 cases (80.57%, 723 eyes) were A-E stage and 81.47% (589/723) were D-E stages of retinoblastoma; extraocular stage was present in 101 cases (120 eyes, 14.76% ); metastatic stage was present in 32 cases (44 eyes, 4.67%). Pathology diagnosis was performed in 494 cases of unilateral or bilateral enucleation; 91 cases were grade I, 260 cases were grade II, 94 cases were grade III, 49 cases were grade IV. The median follow-up time was 27 months until June 2010. Total survival rate was 95.13%. A total of 34 cases were lost to follow-up and 34 cases were abandoned.
CONCLUSIONS: Children developed retinoblastoma at a young age. Early diagnosis is difficult. Key factors of clinical treatment and long survival rate were diagnosis and treatment at the early stage with multidisciplinary methods.

Joyce MJ, Pollock BH, Devidas M, et al.
Chemotherapy for initial induction failures in childhood acute lymphoblastic leukemia: a Children's Oncology Group Study (POG 8764).
J Pediatr Hematol Oncol. 2013; 35(1):32-5 [PubMed] Free Access to Full Article Related Publications
Children with acute lymphocytic leukemia who fail to enter remission have a poor prognosis. In a previous study, 9 of 14 children with induction failure entered remission after teniposide (VM26) plus cytosine arabinoside (Ara-C). We attempted to confirm these results. Twenty children received teniposide (200 mg/m/day IV) for 3 days and cytosine arabinoside (100 mg/m/day continuous IV infusion) for 7 days. There were 3 complete and 3 partial responses. Two additional patients achieved a complete response after a second, shorter course of the same agents. Although VM26 plus Ara-C is an active combination for treatment of acute lymphocytic leukemia induction failure, it does not appear as effective as in the initial report. Better treatments for this problem are needed.

Tamura N, Hirano K, Kishino K, et al.
Analysis of type of cell death induced by topoisomerase inhibitor SN-38 in human oral squamous cell carcinoma cell lines.
Anticancer Res. 2012; 32(11):4823-32 [PubMed] Related Publications
Despite frequent use of topoisomerase inhibitors (TIs) as antitumor agents, their application to oral squamous cell carcinoma (OSCC) has not been reported. We investigated three inhibitors of topoisomerase I [camptothecin, irinotecan, SN-38 (active metabolite of irinotecan)] and two inhibitors of topoisomerase II (etoposide, teniposide) for their cytotoxicity towards a total of 15 human tumor cell lines and normal cultured cells. All TIs exhibited higher cytotoxicity towards tumor cell lines (OSCC, glioblastoma, myelogenous leukemia) as compared with normal mesenchymal (gingival fibroblast, pulp cell, periodontal ligament fibroblast) and epithelial cells (skin keratinocytes). Among TIs, SN-38 had the highest cytotoxicity towards OSCC cell lines, with a tumor specificity index of 1321 compared to mesenchymal cells and 22 compared with epithelial cells. SN-38 induced different types of cell death in two OSCC cell lines: apoptosis (caspase-3 activation and internucleosomal DNA fragmentation) in HSC-2 cells and autophagy (formation of autophagosome and secondary lysosome) in HSC-4 cells. The cell death of HSC-2 and HSC-4 cells was significantly inhibited by pre-treatment with caspase inhibitor (Z-VAD-FMK) and autophagy inhibitors (3-methyladenine, bafilomycin A1), respectively. The present study demonstrated that SN-38 is highly cytotoxic to OSCC cell lines, regardless of the type of induced cell death, suggesting its future application for chemotherapy of OSCC.

Wang Q, Li A, Wang H, Wang J
Knockdown of apoptosis repressor with caspase recruitment domain (ARC) increases the sensitivity of human glioma cell line U251MG to VM-26.
Int J Clin Exp Pathol. 2012; 5(6):555-61 [PubMed] Free Access to Full Article Related Publications
Previous studies have demonstrated that apoptosis repressor with caspase recruitment domain (ARC) is up-regulated in many forms of malignant tumors and low levels of ARC protein were expressed in normal human brain tissue. Little is known expression of ARC in glioma. Here, we found that ARC protein was highly expressed in primary human glioma when compared with normal brain tissues. A decrease in cell viability and an increase in apoptosis were observed in U251MG cells after ARC was knocked down. Knockdown of ARC was confirmed by western blotting. Knockdown of ARC promoted caspase-8, caspase-3 activation and Bax accumulation. These results indicate that ARC has a anti-apoptosis function in glioma.

Ezoe S
Secondary leukemia associated with the anti-cancer agent, etoposide, a topoisomerase II inhibitor.
Int J Environ Res Public Health. 2012; 9(7):2444-53 [PubMed] Free Access to Full Article Related Publications
Etoposide is an anticancer agent, which is successfully and extensively used in treatments for various types of cancers in children and adults. However, due to the increases in survival and overall cure rate of cancer patients, interest has arisen on the potential risk of this agent for therapy-related secondary leukemia. Topoisomerase II inhibitors, including etoposide and teniposide, frequently cause rearrangements involving the mixed lineage leukemia (MLL) gene on chromosome 11q23, which is associated with secondary leukemia. The prognosis is extremely poor for leukemias associated with rearrangements in the MLL gene, including etoposide-related secondary leukemias. It is of great importance to gain precise knowledge of the clinical aspects of these diseases and the mechanism underlying the leukemogenesis induced by this agent to ensure correct assessments of current and future therapy strategies. Here, I will review current knowledge regarding the clinical aspects of etoposide-related secondary leukemia, some probable mechanisms, and strategies for treating etoposide-induced leukemia.

Sun P, Liu Y, Ying H, Li S
Action of db-cAMP on the bystander effect and chemosensitivity through connexin 43 and Bcl-2-mediated pathways in medulloblastoma cells.
Oncol Rep. 2012; 28(3):969-76 [PubMed] Related Publications
Medulloblastoma (MB) is one of the most common malignant brain tumors of childhood and is associated with a poor prognosis. Gap-junctional intercellular communication (GJIC) is an important mode for cell-to-cell communication. Dysfunctional GJIC is exhibited in most cancer cells. There is significant evidence that GJIC is important in at least some prodrug/suicide gene systems by augmenting the bystander effect (BE). GJIC is made up of connexins (Cxs), among which Cx43 is present in most tissues. Bcl-2, an important apoptosis blocker, is closely associated with the sensitivity to anticancer drugs. Our study showed that dibutyryl cyclic adenosine monophosphate (db-cAMP) upregulated the Cx43 expression and GJIC function in Daoy medulloblastoma cells. It directly enhanced the BE using a herpes simplex virus thymidine kinase (HSV‑tk)/ganciclovir (GCV) system, which was blocked by a Cx43 inhibitor. In addition, db-cAMP increased the cytotoxicity of temozolomide and teniposide, possibly by downregulating the Bcl-2 expression and inducing apoptosis. Taken together, we demonstrated the beneficial effect of db-cAMP in treating medulloblastoma depending on the upregulation of BE and chemosensitivity through Cx43 and Bcl-2-mediated pathways.

Reveiz L, Rueda JR, Cardona AF
Chemotherapy for brain metastases from small cell lung cancer.
Cochrane Database Syst Rev. 2012; (6):CD007464 [PubMed] Related Publications
BACKGROUND: Small cell lung cancer (SCLC) accounts for approximately 20% of all cases of lung cancer. It tends to disseminate early in the course of its natural history and to grow quickly. Approximately 10% to 18% of patients present with brain metastases (BM) at the time of initial diagnosis, and an additional 40% to 50% will develop BM some time during the course of their disease.
OBJECTIVES: The aim of this review was to evaluate the effectiveness and toxicity of systemic chemotherapy for the treatment of BM from SCLC.
SEARCH METHODS: We searched the Cochrane Lung Cancer Review Group Specialised Register (July 2011), CENTRAL (2011, Issue 5), PubMed (1966 to July 2011), EMBASE (2005 to July 2011), LILACS (1982 to July 2011) and the International Clinical Trial Registry Platform (ICTRP).
SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing systemic chemotherapy (single agent or combination chemotherapy) with another chemotherapy regimen, palliative care, whole brain radiotherapy or any combination of these interventions for the treatment of BM as the only site of progression.
DATA COLLECTION AND ANALYSIS: Data extraction and 'Risk of bias' assessment were carried out independently by two review authors. As the included studies evaluated three different treatment modalities meta-analysis was not possible.
MAIN RESULTS: Three RCTs, involving 192 participants, met inclusion criteria for this review. No significant differences for overall survival (OS) were reported in any of the trials: in the first trial, 33 patients received whole brain radiation therapy and no significant difference was found between patients treated with topotecan and those not treated with topotecan. In a second trial, in which 120 patients were randomized to receive teniposide with or without brain radiation therapy, the authors reported that the median progression-free survival (brain-specific progression-free survival (PFS)) was 3.5 months in the combined modality arm and 3.2 in the teniposide alone arm. In a third trial, comparing sequential and concomitant chemoradiotherapy (teniposide plus cisplatin) in 39 participants, the survival difference between the two groups was not statistically significant. While the first trial reported no significant difference in PFS, the second RCT found a significant difference favoring combined therapy group. The second trial also found that patients receiving chemoradiotherapy (teniposide plus whole brain radiotherapy) had a higher complete response rate than those receiving only the topoisomerase inhibitor.
AUTHORS' CONCLUSIONS: Given the paucity of robust studies assessing the clinical effects of treatments, available evidence is insufficient to judge the effectiveness and safety of chemotherapy for the treatment of BM from SCLC. Published studies are insufficient to address the objectives of this review. According to the available evidence included in this review, chemotherapy does not improve specific brain PFS and OS in patients with SCLC. The combined treatment of teniposide and brain radiation therapy contributed to outcome in terms of increased complete remission and shorter time to progression (though not OS).

Wang B, Ren C, Zhang W, et al.
Intensified therapy followed by autologous stem-cell transplantation (ASCT) versus conventional therapy as first-line treatment of follicular lymphoma: a meta-analysis.
Hematol Oncol. 2013; 31(1):29-33 [PubMed] Related Publications
There are two different international standards for the treatment of follicular lymphoma (FL): intensified therapy followed by autologous stem-cell transplantation (ASCT) and conventional therapy in the first-line setting. However, their role remains unclear. Our aim was to define the treatment effect of intensified therapy followed by ASCT compared with conventional therapy as first-line treatment of patients with FL in terms of overall survival (OS) and event-free survival (EFS). We searched for randomised controlled trials in Medline, Embase, the Cochrane controlled trials register and the Science Citation Index (1985 to June 2011). Effect measures used were hazard ratios (HR) for OS, EFS and secondary tumour rate. Two independent review authors extracted data and assessed quality of trials. Four trials were identified, covering a total of 941 subjects. The random-effects summary HR by comparing the treatment effect on OS between intensified and conventional therapy was 0.95 [0.70, 1.30] (p = 0.75), indicating that no additional survival benefit was derived from the intensified therapy followed by ASCT. A significant benefit of intensified therapy followed by ASCT as first-line treatment was detected in terms of EFS: the random-effects summary HR (intensified versus conventional therapy) was 0.59 [0.44, 0.79] (p < 0.001). This meta-analysis showed that despite its superior EFS, intensified therapy followed by ASCT does not improve the OS compared with conventional therapy.

Hou Y, Wang HQ, Ba Y
Comparison on therapeutic effects of RFT and RCTVP regimen in the treatment of patients with indolent B-cell lymphoma in China.
Med Oncol. 2012; 29(4):2372-8 [PubMed] Related Publications
To compare the efficacy and safety of RFT (retuximab, fludarabine, pirarubicin) with RCTVP (retuximab, cyclophophamide, pirarubicin, vindesine and prednisone) in 248 indolent B-cell non-Hodgkin's lymphoma (NHL) patients. Two hundred and forty-eight patients with indolent B-cell NHL were treated with combined chemotherapy, including RFT and RCTVP, from January 2002 to December 2010 in Tianjin Cancer Hospital. The rate of response, toxicity and long-term survival for the two regimens were analyzed retrospectively. For the previously untreated patients, overall response rate for RFT arm and RCTVP arm was 71.7 and 70.6%, and complete response rate was 47.5 and 54.9%, respectively (P>0.05). For the refractory and relapsed patients, overall response (OR) rate and complete response (CR) rate were significantly improved in the RFT arm versus the RCTVP arm (P<0.05). There were no statistically significant differences in overall survival (OS) between treatment groups. Comparing with RCTVP regimen, fludarabine-based treatment was associated with superior PFS both in previously untreated, refractory and relapsed patients. WHO grades 3 and 4 hematological adverse events were more common in the RFT arm. Neurotoxicity was more common in the RCTVP arm. For the previously untreated patients, there was no difference between RFT arm and RCTVP arm on OR and CR rates. For the refractory and relapsed indolent B-cell NHL patients who received RFT regimen achieved higher OR and CR rates compared with RCTVP-treated patients. No differences in OS were noted. RFT regimen was associated with superior PFS both in previously untreated, refractory and relapsed patients. RFT regimen is effective and well tolerated for patients with untreated, refractory and relapsed indolent B-cell NHL.

Leone G, Fianchi L, Voso MT
Therapy-related myeloid neoplasms.
Curr Opin Oncol. 2011; 23(6):672-80 [PubMed] Related Publications
PURPOSE OF REVIEW: The purpose of this review is to update knowledge on therapy-related myeloid neoplasms (t-MN), taking into account the new 2008 WHO classification, new genome-wide approaches for the definition of susceptibility towards t-MN and the introduction of new more aggressive treatments in cancer patients.
RECENT FINDINGS: t-MN are an increasing matter in cancer survivors treated with chemoradiotherapy. One of the major concerns in hematologic malignancies is childhood acute lymphoblastic leukemia, in which the leukemogenic role of extended etoposide/teniposide treatment, concomitant intensive antimetabolite and asparaginase, granulocyte colony-stimulating factor (G-CSF) and prophylactic cranial radiotherapy use have been established. In high-risk Hodgkin lymphoma, 3% t-MN have been observed at 10-year follow-up with the escalated bleomycin/etoposide/doxorubicin/cyclophosphamide/vincristine/procarbazine/prednisone (BEACOPP) schedule, versus 0.4% with doxorubicin/bleomycin/vinblastine/dacarbazine (ABVD). In lymphoproliferative diseases the new drugs fludarabine and lenalidomide may increase the risk of second tumors, when associated to other cytotoxic therapies. Among solid tumors, breast cancer is most frequently associated to t-MN. The risk is correlated to higher chemotherapy doses, radiotherapy, use of G-CSF, but also independent from treatment, suggesting a genetic predisposition to both diseases. Radiotherapy plays a role also in female pelvic tumors and in testicular cancer, when associated to cisplatin.
SUMMARY: The risk of t-MN is not negligible, although below 2% in most series. This is particularly significant for younger cancer patients and during the first 5 years after the primary malignancies. Efforts should be maximized to identify susceptibility factors to identify patients at risk, in whom more leukemogenic drugs and schedules should be avoided.

Chai H, Liu M, Tian R, et al.
miR-20a targets BNIP2 and contributes chemotherapeutic resistance in colorectal adenocarcinoma SW480 and SW620 cell lines.
Acta Biochim Biophys Sin (Shanghai). 2011; 43(3):217-25 [PubMed] Related Publications
Chemotherapy is an important treatment for colorectal adenocarcinoma cancer; however, colorectal adenocarcinoma cells often develop resistance to chemotherapeutic drugs, leading to relapse and poor patient prognosis. The development of drug resistance is often a multifactor process, which involved several genes and cellular mechanisms. microRNAs are endogenous small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. In the present study, we investigated the possible role of microRNAs in regulating drug sensitivity of colorectal adenocarcinoma cells SW620 and SW480. Using microRNA expression arrays and quantitative reverse transcriptase (RT)-PCR, we found that SW620 cells exhibited elevated miR-20a expression compared with SW480 cells. In addition, these two cell lines displayed different sensitivities to the chemotherapeutic drugs fluorouracil, oxaliplatin, and teniposide. Modulation of miR-20a altered the sensitivity of SW620 and SW480 cells to these drugs; knockdown of miR-20a sensitized SW620 cells to chemotherapeutic agents, whereas overexpression of miR-20a in SW480 cells resulted in chemoresistance. Endogenous BNIP2 mRNA and BNIP2 protein levels were inversely related to miR-20a levels as detected by quantitative RT-PCR and western blot analysis. Fluorescence reporter assays showed a direct interaction between miR-20a and the BNIP2 3'UTR. Taken together, our findings suggested that miR-20a may play a role in colorectal adenocarcinoma cancer cell drug resistance and may be a therapeutic target against chemotherapy drug resistance in colorectal adenocarcinoma.

Bozinov O, Kalk JM, Krayenbühl N, et al.
Decreasing expression of the interleukin-13 receptor IL-13Ralpha2 in treated recurrent malignant gliomas.
Neurol Med Chir (Tokyo). 2010; 50(8):617-21 [PubMed] Related Publications
The IL-13Ralpha2 gene encodes for a 65 kDa protein that forms one of the subunits of the interleukin-13 (IL-13) receptor. This gene is highly expressed in various types of human tumors including malignant gliomas. The expression level of IL-13Ralpha2 was examined in a total of 45 tissue samples of anaplastic astrocytomas (AAs) World Health Organization (WHO) grade III, glioblastomas (GBMs) WHO grade IV, and first-recurrent glioblastomas (frGBMs) after treatment with radiation and chemotherapy. IL-13Ralpha2 expression was detected by semiquantitative reverse transcription real-time polymerase chain reaction (PCR) using ABI PRISM 7700 and Qiagen QuantiTect SYBR Green PCR kits. The expression level of IL-13Ralpha2 (15 fold) was significantly reduced in frGBMs compared to the primary GBMs (p = 0.014), and significantly reduced by more than 15 fold (p = 0.003) in all untreated malignant astrocytomas (AAs and GBMs) compared with treated frGBMs. Expression of IL-13Ralpha2 seems to be lower in frGBMs compared to GBMs. The promising antitumor effect of IL-13 cytotoxin could be greatly reduced in frGBM or only achievable with higher amounts of cytotoxin, due to the significantly lower expression of the cytotoxin's target structure.

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