Investigational New Drugs (INVEST NEW DRUG)

Publications in this journal

• Article: Phase II study of gemcitabine in combination with vinorelbine versus gemcitabine followed by vinorelbine for metastatic breast cancer

  In Hae Park, Jungsil Ro, Keun Seok Lee, Shi Nae Kim, Young Ho Yun, Byung Ho Nam
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  ABSTRACT: Background No clear data are available concerning the superiority of combination chemotherapy to sequential therapy using agents beyond 1st or 2nd line chemotherapy for treating patients with metastatic breast cancer. Methods Patients were randomized to receive a combination of gemcitabine and vinorelbine or gemcitabine until disease progression followed by vinorelbine monotherapy. Quality of life was assessed using EORTC QLQ-C30 questionnaires. Results Forty-two patients were randomized to the combination arm and 40 were randomized to the sequential arm. Baseline characteristics were well balanced between the arms. The median number of chemotherapy cycles was 4 (range, 1–23) for the combination arm and 6 (range, 1–25) for the sequential arm. Patients receiving combination therapy had a higher composite response rate (26.8% vs. 12.5%; P = 0.106) but a shorter median time to treatment failure (3.6 vs. 4.4months, P = 0.252) as compared to patients receiving sequential monotherapy. Median overall survival for the combination and sequential arms was 10.6months and 8.9months, respectively (P = 0.436). Toxicities were manageable and similar in both arms. Quality of life measurements in global health, role, and social function were superior in the combination arm (P < 0.05). Conclusions Combined gemcitabine and vinorelbine therapy appears comparable to sequential monotherapy for heavily pretreated patients with metastatic breast cancer as demonstrated by improved quality of life outcomes with similar therapeutic efficacies and incidences of adverse events. KeywordsBreast cancer-Gemcitabine-Vinorelbine-Quality of life
  Investigational New Drugs 05/2012; 28(5):659-669.
• Article: A phase I evaluation of the combination of vinflunine and erlotinib in patients with refractory solid tumors

  Hanna K. Sanoff, Janine M. Davies, Christine Walko, William Irvin, Larry Buie, Kimberly Keller, Anastasia Ivanova, Wing-Keung Chiu, Bert H. O’Neil, Thomas E. Stinchcombe, E. Claire Dees
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  ABSTRACT: Purpose. Epidermal growth factor receptor (EGFR) inhibition may overcome chemotherapy resistance by inhibiting important anti-apoptotic signals that are constitutively activated by an overstimulated EGFR pathway. Methods. This phase I dose escalation trial assessed the safety and efficacy of vinflunine, a novel vinca alkaloid microtubule inhibitor, with erlotinib, an EGFR tyrosine kinase inhibitor, in patients with refractory solid tumors. Results. Seventeen patients were treated, 10 with continuous erlotinib, and 7 with intermittent erlotinib. At dose level 1, vinflunine 280mg/m2 IV day 1 and erlotinib 75mg PO days 2–21 (“continuous erlotinib”) in 21day cycles, two of four patients experienced DLTs. At dose level −1 (vinflunine 250mg/m2 every 21days and erlotinib 75mg/day), two of six patients experienced DLTs. The study was amended to enroll to “intermittent erlotinib” dosing: vinflunine day 1 and erlotinib days 2–15 of a 21day cycle. Two of seven experienced DLTs and the study was terminated. One patient with breast cancer had a partial response; three had stable disease ≥6 cycles. All were treated in the continuous erlotinib group. Conclusions. Given the marked toxicity in our patient population, the combination of vinflunine and erlotinib cannot be recommended for further study with these dosing schemas. KeywordsInflunine–Erlotinib–Phase I–Safety and toxicity
  Investigational New Drugs 04/2012; 29(5):978-983.
• Article: Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice

  Jimmie Colon, Md. Riyaz Basha, Rafael Madero-Visbal, Santhi Konduri, Cheryl H. Baker, Luis J. Herrera, Stephen Safe, David Sheikh-Hamad, Ala Abudayyeh, Beatrice Alvarado, Maen Abdelrahim
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  ABSTRACT: The nonsteroidal anti-inflammatory drug (NSAID), tolfenamic acid (TA) is emerging as a new anti-cancer agent. TA induces the degradation of specific Specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 which are associated with tumor growth and metastasis. In this study we have evaluated the effect of TA on lung cancer using both in vitro and in vivo models. TA in a dose dependent manner inhibited proliferation and cell viability of two different lung cancer cells, A549 and CRL5803. TA treatment for 48h significantly decreased the expression of Sp1, Sp3 and Sp4. The hepatocyte growth factor receptor, c-Met is overexpressed in a variety of cancers including lung cancer and Sp proteins mediate the regulation of c-Met. TA diminished the expression of c-Met protein and modulates its downstream signaling pathway. Furthermore, TA treatment significantly increased the number of apoptotic cells and pro-apoptotic markers c-PARP and Bax confirming the activation of apoptotic pathways. In vivo studies using the orthotopic mice model for lung cancer showed that TA (25mg/kg/2days and 50mg/kg/2days) resulted in a dose dependent decrease in tumor formation. The immunohistochemical staining of lung tissue showed high expression of Sp1, Sp3, Sp4, c-Met and phospho Met in control group and a dose dependent decrease in TA treated groups. The crucial findings of this study support that targeting c-Met with a potent inhibitor of Sp proteins is a robust strategy for the implications in lung cancer treatment and TA can serve as a therapeutic agent for this devastating disease. KeywordsTolfenamic acid–c-Met–Sp proteins–Lung cancer–Tumor inhibition
  Investigational New Drugs 04/2012; 29(1):41-51.
• Article: Phase I trial of vinflunine and pemetrexed in refractory solid tumors

  Hanna K. Sanoff, Janine Davies, Christine Walko, Larry Buie, Wing-Keung Chiu, Anastasia Ivanova, Bert O’Neil, Thomas E. Stinchcombe, Kimberly Keller, E. Claire Dees
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  ABSTRACT: Background Vinflunine is a novel vinca alkaloid with promising single agent clinical activity. Pemetrexed has at least additive activity with other vincas. A phase I trial was undertaken to assess the safety of vinflunine and pemetrexed in patients with refractory solid tumors. Methods A standard 3-patient cohort dose escalation scheme was used to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of the vinflunine/pemetrexed combination. Pemetrexed 500mg/m2 was given with vinflunine 280mg/m2 (cohort 1), 300mg/m2 (cohort 2) or 320mg/m2 (cohort 3) on day 1 of a 21-day cycle. Results 19 patients were enrolled, median age 58years (range 32 to 77) and had a median of 3 (range 1–6) prior therapies. DLT occured 1 of 6 pts in cohort 1 (thrombocytopenia, hyponatremia), 2 of 10 pts in cohort 2 (febrile neutropenia, hyponatremia, hyperbilirubinema; febrile neutropenia), and 2 of 3 pts in cohort 3 (febrile neutropenia, hypokalemia; febrile neutropenia). 1pt in cohort 2 died prior to completion of cycle 1 likely from disease progression. Most common grade 3/4 adverse events were neutropenia (7), leukopenia (5). Febrile neutropenia occurred in 4 patients (21%). No objective responses were seen. Two patients (breast and lung) had prolonged stable disease for 25 and 20 cycles respectively. Conclusions Based on this experience we recommend vinflunine 300mg/m2 and pemetrexed 500mg/m2 in combination every 3weeks for future study. At these doses, the combination of vinflunine and pemetrexed was tolerable in this heavily pretreated population. Hematologic toxicity, including febrile neutropenia, was prominent. KeywordsPhase I–Vinflunine–Pemetrexed–Vinca alkaloid
  Investigational New Drugs 04/2012; 29(1):131-136.
• Article: A prospective phase II study of cetuximab in combination with XELOX (capecitabine and oxaliplatin) in patients with metastatic and/or recurrent advanced gastric cancer

  Chul Kim, Jae-Lyun Lee, Min-Hee Ryu, Heung Moon Chang, Tae Won Kim, Ho Young Lim, Hye Jin Kang, Young Suk Park, Baek-Yeol Ryoo, Yoon-Koo Kang
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  ABSTRACT: Background We evaluated the efficacy and safety of cetuximab in combination with XELOX [XELoda® (capecitabine) and OXaliplatin] in advanced gastric cancer (AGC) patients. The objectives were to evaluate overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of cetuximab plus XELOX. Methods Previously untreated AGC patients received intravenous infusion of cetuximab 400mg/m2 on day 1 followed by weekly infusions of 250mg/m2. Oxaliplatin 130mg/m2 was administered intravenously on day 1 and capecitabine 1,000mg/m2 bid was administered orally for 14days of a 3-week cycle. Chemotherapy was given until disease progression or intolerable toxicities. On completing maximum 8 cycles of chemotherapy, patients were allowed weekly cetuximab until progression. Response evaluations were done every two cycles and toxicities were assessed at each visit. Results Forty-four patients (29 male) were enrolled; median age was 57.5years (range 36-70). In total, 253 cycles of XELOX chemotherapy (range 1–8, median 6.5 cycles) and 917 cetuximab infusions (range 1–58, median 19.0) were delivered. Overall RR was 52.3%. Median PFS and OS were 6.5months (95% CI, 4.9–8.4) and 11.8months (95% CI, 6.7–16.8), respectively. The most common toxicities of all grades were anemia (81.8% of patients), asthenia (81.8%), anorexia (79.6%), hand-foot syndrome (79.6%), acneiform skin eruption (77.2%), and sensory neuropathy (75.0%), and they were mostly grade 1 or 2. Grade 3–4 hematologic toxicities were uncommon (anemia, 6.8%; thrombocytopenia, 2.3%). Conclusions Cetuximab in combination with XELOX chemotherapy was active and safe as first-line treatment of metastatic and/or recurrent AGC patients. KeywordsCetuximab–Targeted therapy–Capecitabine–Oxaliplatin–Gastric cancer
  Investigational New Drugs 04/2012; 29(2):366-373.
• Article: A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma

  Evan M. Hersh, Steven J. O’Day, John Powderly, Khuda D. Khan, Anna C. Pavlick, Lee D. Cranmer, Wolfram E. Samlowski, Geoffrey M. Nichol, Michael J. Yellin, Jeffrey S. Weber
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  ABSTRACT: Objective: Ipilimumab is a fully human, anti–cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibody that has demonstrated antitumor activity in advanced melanoma. We evaluated the safety and efficacy of ipilimumab alone and in combination with dacarbazine (DTIC) in patients with unresectable, metastatic melanoma. Methods: Chemotherapy-naïve patients were randomized in this multicenter, phase II study to receive ipilimumab at 3mg/kg every 4weeks for four doses either alone or with up to six 5-day courses of DTIC at 250mg/m2/day. The primary efficacy endpoint was objective response rate. Results: Seventy-two patients were treated per-protocol (ipilimumab plus DTIC, n = 35; ipilimumab, n = 37). The objective response rate was 14.3% (95% CI, 4.8–30.3) with ipilimumab plus DTIC and was 5.4% (95% CI, 0.7–18.2) with ipilimumab alone. At a median follow-up of 20.9 and 16.4months for ipilimumab plus DTIC (n = 32) and ipilimumab alone (n = 32), respectively, median overall survival was 14.3months (95% CI, 10.2–18.8) and 11.4months (95% CI, 6.1–15.6); 12-month, 24-month, and 36-month survival rates were 62%, 24% and 20% for the ipilimumab plus DTIC group and were 45%, 21% and 9% for the ipilimumab alone group, respectively. Immune-related adverse events were, in general, medically manageable and occurred in 65.7% of patients in the combination group versus 53.8% in the monotherapy group, with 17.1% and 7.7% ≥grade 3, respectively. Conclusion: Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC. KeywordsMetastatic melanoma–Ipilimumab–CTLA-4–Immune therapy–Dacarbazine
  Investigational New Drugs 04/2012; 29(3):489-498.
• Article: Modulation of P-gp expression by lapatinib

  Gráinne Dunne, Laura Breen, Denis M. Collins, Sandra Roche, Martin Clynes, Robert O’Connor
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  ABSTRACT: Chemotherapy drug resistance is a major obstacle in the treatment of cancer. It can result from an increase in levels of cellular drug efflux pumps, such as P-glycoprotein (P-gp). Lapatinib, a growth factor receptor tyrosine kinase inhibitor, is currently in clinical trials for treatment of breast cancer. We examined the impact of co-incubation of chemotherapy drugs in combination with lapatinib in P-gp over-expressing drug resistant cells. Unexpectedly, lapatinib treatment, at clinically relevant concentrations, increased levels of the P-gp drug transporter in a dose- and time-responsive manner. Conversely, exposure to the epidermal growth factor (EGF), an endogenous growth factor receptor ligand, resulted in a decrease in P-gp expression. Despite the lapatinib-induced alteration in P-gp expression, use of accumulation, efflux and toxicity assays demonstrated that the induced alteration in P-gp expression by lapatinib had little direct impact on drug resistance. KeywordsDrug resistance–Lapatinib–P-glycoprotein–Lung cancer
  Investigational New Drugs 04/2012; 29(6):1284-1293.
• Article: Effect of a Vitamin D3 derivative (B3CD) with postulated anti-cancer activity in an ovarian cancer animal model

  Thilo S. Lange, Ashley R. Stuckey, Katina Robison, Kyu Kwang Kim, Rakesh K. Singh, Christina A. Raker, Laurent Brard
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  ABSTRACT: The objective of the present study was to test the hypothesis that Calcidiol derivative B3CD qualifies as a potential anti-cancer drug in vivo employing an ovarian cancer xenograft model in mice. In addition, the selectivity of B3CD on viability and proliferation of platinum-resistant human ovarian cancer cell lines in comparison to control cell lines was analyzed in vitro. B3CD displayed cell line-specific cytotoxicity screened against a panel of ovarian and other carcinoma cell lines, endothelial and control cells. B3CD, at sub-cytotoxic concentrations, revealed stronger effects on the proliferation of SKOV-3 ovarian cancer cells vs. primary fibroblasts as determined by BrdU incorporation analysis. Treatment with B3CD at 0.5µM resulted in highly condensed chromatin and fragmented nuclei in SKOV-3 cells but not in primary fibroblasts. B3CD induced cell death at low drug concentrations (≤0.5µM) in SKOV-3 ovarian cancer cells is mediated by the p38 MAPK signaling pathway: B3CD induced p38 MAPK expression and activation in SKOV-3 cells and inhibition of p38 signaling counteracted B3CD induced cell death in vitro. An ovarian cancer cell animal model (human SKOV-3 cell derived xenografts in nude mice) revealed that tumor growth in few B3CD treated mice accelerated while the majority of B3CD treated mice displayed delayed tumor growth or full tumor regression. B3CD possesses anti-ovarian cancer properties in vitro and in vivo. We propose the further development of non-calcemic bromoacetoxy derivatives of vitamin D3 as potential anti-cancer therapeutics. KeywordsCalcidiol-derivative B3CD-Ovarian cancer-MAPK-signaling-SKOV-3 xenograft model
  Investigational New Drugs 04/2012; 28(5):543-553.
• Article: Characterization of the cell growth inhibitory effects of a novel DNA-intercalating bipyridyl-thiourea-Pt(II) complex in cisplatin-sensitive and—resistant human ovarian cancer cells

  Gaetano Marverti, Alessio Ligabue, Monica Montanari, Davide Guerrieri, Matteo Cusumano, Maria Letizia Di Pietro, Leonarda Troiano, Elena Di Vono, Stefano Iotti, Giovanna Farruggia, Federica Wolf, Maria Giuseppina Monti, Chiara Frassineti
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  ABSTRACT: The cellular effects of a novel DNA-intercalating agent, the bipyridyl complex of platinum(II) with diphenyl thiourea, [Pt(bipy)(Ph2-tu)2]Cl2, has been analyzed in the cisplatin (cDDP)—sensitive human ovarian carcinoma cell line, 2008, and its—resistant variant, C13* cells, in which the highest accumulation and cytotoxicity was found among six related bipyridyl thiourea complexes. We also show here that this complex causes reactive oxygen species to form and inhibits topoisomerase II activity to a greater extent in the sensitive than in the resistant line. The impairment of this enzyme led to DNA damage, as shown by the comet assay. As a consequence, cell cycle distribution has also been greatly perturbed in both lines. Morphological analysis revealed deep cellular derangement with the presence of cellular masses, together with increased membrane permeability and depolarization of the mitochondrial membrane. Some of these effects, sometimes differentially evident between the two cell lines, might also be related to the decrease of total cell magnesium content caused by this thiourea complex both in sensitive and resistant cells, though the basal content of this ion was higher in the cDDP-resistant line. Altogether these results suggest that this compound exerts its cytotoxicity by mechanisms partly mediated by the resistance phenotype. In particular, cDDP-sensitive cells were affected mostly by impairing topoisomerase II activity and by increasing membrane permeability and the formation of reactive oxygen species; conversely, mitochondrial impairment appeared to play the most important role in the action of complex F in resistant cells. KeywordsCisplatin-resistance–DNA intercalators–Ovarian cancer cells–Topoisomerase II–Mg2+ content
  Investigational New Drugs 04/2012; 29(1):73-86.
• Article: A phase I study of continuous infusion cilengitide in patients with solid tumors

  Peter H. O’Donnell, Samir D. Undevia, Walter M. Stadler, Theodore M. Karrison, M. Kelly Nicholas, Linda Janisch, Mark J. Ratain
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  ABSTRACT: Background: Cilengitide (EMD121974) is a cyclized pentapeptide that is a potent and selective integrin antagonist which has shown activity in malignant gliomas. In all previous studies, cilengitide has been administered in an intermittent fashion. However, cilengitide has a short half-life of 3–5h with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion cilengitide. Methods: Cilengitide was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2h after infusion bag change. Results: Thirty-five patients were treated (median age 56; 23 males) at dose levels of 1, 2, 4, 8, 12, 18, 27, and 40mg/h. Toxicities were limited to grade ≤2 and showed no relation to dose. Fatigue was most common (17%), while all other toxicities were reported in <10% of patients. No dose-limiting toxicities were observed, and therefore the maximum tolerated dose was not reached. Pharmacokinetic analysis showed that values for clearance and volume of distribution were comparable across dose levels, and the steady-state concentration increased proportionally with dose. Conclusions: Cilengitide can be safely administered as a continuous infusion at doses up to at least 40mg/h, which represents the maximum feasible dose due to drug solubility and delivery limitations. The pharmacokinetics of continuous infusion cilengitide are linear and consistent with the results obtained using a twice weekly infusion. KeywordsCilengitide–EMD121974–Continuous infusion
  Investigational New Drugs 04/2012; 30(2):604-610.
• Article: Bevacizumab for salvage treatment of metastatic breast cancer: a systemic review and meta-analysis of randomized controlled trials

  Jae-Bok Lee, Ok Hee Woo, Kyong Hwa Park, Sang Uk Woo, Dae Sik Yang, Ae-Ree Kim, Eun Sook Lee, Yeul Hong Kim, Jun Suk Kim, Jae Hong Seo
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  ABSTRACT: Although various new agents have been developed for the treatment of patients with metastatic breast cancer (MBC), overall survival rates have changed little in the last half century. We conducted meta-analysis to verify the clinical efficacy of bevacizumab for the salvage treatment of MBC. Event-based hazard ratios (HR) with 95% confidence intervals (95% CIs) were derived, and a test of heterogeneity was applied. Four studies, with a total of 2,860 patients, met the inclusion criteria for analysis. The pooled results of clinical efficacies were: HR for progression free survival 0.69 (95% CI, 0.58–0.81, z = 4.54, P <0.001); HR for overall survival 0.92 (95% CI, 0.82–1.03, z =1.44, P = 0.15); and HR for the clinical objective response rate 1.53 (95% CI, 1.37–1.71, z = 7.37, P < 0.001). In terms of overall survival, subgroup analysis demonstrated statistically significant improvement for the bevacizumab combination in the initial therapy subgroup (HR, 0.878; 95% CI, 0.771–0.999, z = 1.98, P = 0.048). Hypertension and proteinura were more common in the bevacizumab combination arm; however, these toxicities were managed with therapy. In conclusion, meta-analysis suggested benefits of a carefully managed bevacizumab-containing salvage regimen for patients with histologically or cytologically confirmed Her-2 negative MBC who have not received previous cytotoxic therapy. This treatment could improve both progression free survival and overall survival rates. KeywordsBevacizumab–Metastatic breast cancer–Meta-analysis–Salvage treatment
  Investigational New Drugs 04/2012; 29(1):182-188.
• Article: Enhanced cell cycle perturbation and apoptosis mediate the synergistic effects of ST1926 and ATRA in neuroblastoma preclinical models

  Angela Maria Di Francesco, Paolo Ubezio, Anna Rita Torella, Daniela Meco, Filomena Pierri, Giuseppe Barone, Gabriella Cusano, Claudio Pisano, Maurizio D’Incalci, Riccardo Riccardi
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  ABSTRACT: Retinoic acid therapy is nowadays an important component of treatment for residual disease of stage IV neuroblastoma after Retinoic acid therapy is nowadays an important component of treatment for residual disease of stage IV neuroblastoma after multimodal therapy. Nevertheless, arising resistance and treatment toxicity could represent relevant limiting factors. In multimodal therapy. Nevertheless, arising resistance and treatment toxicity could represent relevant limiting factors. In the present study, we show that retinoic acid enhances the cytostatic and apoptogenic properties of the novel adamantyl retinoid the present study, we show that retinoic acid enhances the cytostatic and apoptogenic properties of the novel adamantyl retinoid ST1926 in a panel of neuroblastoma cells with different p53 status and caspase 8 expression, resulting in synergistic effects ST1926 in a panel of neuroblastoma cells with different p53 status and caspase 8 expression, resulting in synergistic effects as assessed by Combination Index and Isobologram analysis. Under conditions where the two drugs alone produced no toxic effects, as assessed by Combination Index and Isobologram analysis. Under conditions where the two drugs alone produced no toxic effects, their combination resulted in enhanced G2-M arrest and sub-G1 population as shown by BrdU pulse-chase and labeling experiments. their combination resulted in enhanced G2-M arrest and sub-G1 population as shown by BrdU pulse-chase and labeling experiments. PARP cleavage, caspase 3, 8 and 9 activation and modulation of DR4 and FAS were indicative of enhanced apoptosis triggeredggered by the co-incubation of the two drugs whereas neither ST1926-mediated genotoxic damage nor ATRA-differentiating effects were by the co-incubation of the two drugs whereas neither ST1926-mediated genotoxic damage nor ATRA-differentiating effects were affected by the combined treatment. Caspase-3 and 8-mediated apoptosis appeared to play an important role in the drugs synergism. affected by the combined treatment. Caspase-3 and 8-mediated apoptosis appeared to play an important role in the drugs synergism. In fact, the addition of a pan-caspase inhibitor ZVAD-FMK reverted this effect in SK-N-DZ cells, and synergism was confined In fact, the addition of a pan-caspase inhibitor ZVAD-FMK reverted this effect in SK-N-DZ cells, and synergism was confined to limited drugs doses in HTLA cells not expressing caspase-8. Although not modulated, p53 appeared to enhance cells responsiveness to limited drugs doses in HTLA cells not expressing caspase-8. Although not modulated, p53 appeared to enhance cells responsiveness to retinoid/ATRA combination. In vivo studies in the most sensitive neuroblastoma model SK-N-DZ, confirmed enhanced activity to retinoid/ATRA combination. In vivo studies in the most sensitive neuroblastoma model SK-N-DZ, confirmed enhanced activity of the drugs combination vs single treatments. The study provides important lines of evidence that such a drugs combination of the drugs combination vs single treatments. The study provides important lines of evidence that such a drugs combination could represent a less toxic and more effective approach for maintenance treatment in children with neuroblastoma. could represent a less toxic and more effective approach for maintenance treatment in children with neuroblastoma. KeywordsST1926–Atypical retinoids–ATRA–Neuroblastoma–Drugs synergism KeywordsST1926–Atypical retinoids–ATRA–Neuroblastoma–Drugs synergism
  Investigational New Drugs 04/2012;
• Article: Salvage therapy with gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX) for B-cell non-Hodgkin’s lymphoma: a consortium for improving survival of lymphoma (CISL) trial

  Byeong-Bae Park, Won Seog Kim, Hyeon Seok Eom, Jin Seok Kim, Young Yiul Lee, Suk Joong Oh, Dae Ho Lee, Cheolwon Suh
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  ABSTRACT: Background: We investigated response rates to and toxicities of gemcitabine, ifosfamide, dexamethasone, and oxaliplatin (GIDOX) for the treatment of relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL). Patients and Methods: Patients with recurrent or refractory diffuse large B-cell lymphoma or mantle cell lymphoma (DLBCL) were eligible for enrollment in this study. Treatment consisted of gemcitabine 1,000mg/m2 intravenously (i.v.) on Days 1 and 8, ifosfamide 2,000mg/m2 i.v. on Day 1, dexamethasone 40mg orally on Days 1–4, and oxaliplatin 130mg/m2 i.v. on Day 2, every 21days. The primary goal of treatment was to establish a response rate after three cycles. Afterwards, patients could proceed to high-dose chemotherapy followed by autologous stem cell transplantation (HDC-ASCT) or receive up to six treatment cycles. Results: Twenty-seven eligible patients were evaluated for toxicity and response. The median age of the patients was 54years (range, 18–75years), and most had DLBCL. After three cycles, there were four CR (15%) and 10 PR (37%) for an overall response rate (RR) of 52%. Among a total of 88 GIDOX cycles, grade 3 and 4 neutropenia occurred in 33% and 16% of the cycles, respectively. Likewise, grade 3 and 4 thrombocytopenia occurred in 14% and 16% of the cycles, respectively. Two patients (2%) experienced febrile neutropenia, while seven patients (26%) proceeded to HDC-ASCT. Conclusions: GIDOX is an active salvage regimen for aggressive B-cell NHL and can be tolerated by patients with acceptable toxicity. KeywordsGemcitabine–Salvage therapy–Non-Hodgkin’s lymphoma
  Investigational New Drugs 04/2012; 29(1):154-160.
• Article: N-4-iodophenyl-N′-2-chloroethylurea, a novel potential anticancer agent with colon-specific accumulation: radioiodination and comparative in vivo biodistribution profiles

  Emmanuelle Mounetou, Elisabeth Miot-Noirault, René C. Gaudreault, J. Claude Madelmont
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  ABSTRACT: In a search for more selective anticancer drugs, we have designed nitrogen mustard and nitrosourea conjugates leading to a series of N-4-aryl-N′-2-chloroethylureas (CEUs). The iodinated derivative N-4-iodophenyl-N′-2-chloroethylurea (4-ICEU) has demonstrated significant antineoplastic and antiangiogenic potency in preclinical evaluations. In this study, 4-ICEU was radiolabelled with [125I]iodide in order to carry out a comparative study of its in vivo behavior profile. 4-[125I]-ICEU was synthesized by direct electrophilic radioiodination with 80% radiochemical yield and 97% radiopurity. Three different routes of administration (intraperitoneal (ip), intravenous (iv) and intratumoral (it)) were tested in mice bearing subcutaneously implanted CT-26 murine colon carcinoma. The results clearly established that 4-ICEU was more stable to biotransformation than previously studied CEUs congeners. It was readily bioavailable and reached the CT-26 colorectal tumor regardless of the route of administration. Additionally, the colon mucosa was an important target tissue where 4-ICEU accumulated and remained largely untransformed. In conclusion, these results justify further investigations for developing 4-ICEU as a new chemotherapeutic agent for colorectal cancer. KeywordsChloroethylurea-Anticancer agent-Colon specificity-Radioiodination
  Investigational New Drugs 04/2012; 28(2):124-131.
• Article: TAE226-mediated inhibition of focal adhesion kinase interferes with tumor angiogenesis and vasculogenesis

  Alexander Schultze, Sebastian Decker, Jasmin Otten, Andrea Kristina Horst, Gabi Vohwinkel, Gunter Schuch, Carsten Bokemeyer, Sonja Loges, Walter Fiedler
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  ABSTRACT: Neoangiogenesis plays an important role in tumor growth and metastasis. Evaluation of new anti-angiogenic targets may broaden the armament for future therapeutic concepts. Focal adhesion kinase (FAK), expressed in endothelial and tumor cells, is essential for adhesion and mobility of adherent cells. In the current study we analyzed the anti-angiogenic properties of the FAK inhibitor TAE226 on the proliferation of blood outgrowth endothelial cell (OEC) and differentiation of endothelial progenitor cells (EPC), derived from peripheral blood CD133+ cells, tube formation and on neovascularization in a HT29 xenotransplant model. The effects of TAE226 were compared to those of the rapamycin analogue RAD001. The combination of both drugs was also studied. We showed that HT29 tumor cells and OEC were most sensitive to the action of TAE226 compared to EPC in vitro. In contrast, RAD001 affected the proliferation of both types of endothelial cells stronger than that of HT29 cells. Furthermore we could show that TAE226 inhibited tube formation in a dose dependent manner. In a HT29 subcutaneous tumor model TAE226 and RAD001 diminished MVD at commonly employed doses to a similar degree. Combination of both compounds did not show synergy in vitro or in vivo. Since TAE226 has been shown to inhibit the PI3 kinase, Akt kinase, mTor pathway, addition of RAD001 may not increase this effect. In conclusion, we have shown that treatment with TAE leads to a reduction of neoangiogenesis in vitro and in a mouse model. The effects are mediated by inhibition of angiogenesis and vasculogenic OEC and EPC. KeywordsVasculogenesis-Angiogenesis-Focal adhesion kinase-TAE226-OEC-EPC
  Investigational New Drugs 04/2012; 28(6):825-833.
• Article: Ongoing DNA synthesis in the rat cerebral cortex is regulated by a proteolytic pathway independent of the proteasome and calpains

  J. Sebastián Yakisich, Åke Sidén, Mabel Cruz
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  ABSTRACT: By using mini-units of tissue and protease inhibitors in short term incubation (0–180min), we studied the role of proteolysis for ongoing DNA replication in the developing rat cerebral cortex. The protease inhibitors TLCK, TPCK, PMSF, MG-132 and PSI markedly inhibited DNA synthesis. The inhibitory effects were concentration-dependent and of early onset (within 60min). The most selective proteasome inhibitors lactacystin and clasto-lactacystin-β-lactone as well as the calpain inhibitor I and II had no or minimal effects on DNA synthesis. Only high concentrations of calpain inhibitor I (≥ 250μM) and calpain inhibitor II (≥ 500μM) gave a DNA synthesis inhibition. These results suggest that (1) ongoing DNA replication is regulated by proteolysis and (2) the proteolytic pathways involved are neither the proteasome nor the calpains. KeywordsCerebral cortex-DNA synthesis-Protease inhibitors-Proteasome-Calpains
  Investigational New Drugs 04/2012; 28(3):242-250.
• Article: Strong inhibition of replicative DNA synthesis in the developing rat cerebral cortex and glioma cells by roscovitine

  Juan Sebastian Yakisich, Marina Fernanda Vita, Åke Siden, Deborah Ruth Tasat, Mabel Cruz
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  ABSTRACT: The effects of the cyclin-dependent kinase inhibitors roscovitine and olomoucine on DNA synthesis rate during normal rat brain development were studied by using short time (90min) incubation. Both purine analogues at 100 μM concentration decreased the DNA synthesis of rat cerebral cortex in an age-dependent manner. The maximun inhibitory effect (~ 90% for roscovitine, ~ 60% for olomoucine) occurred in rats of 2–13days postnatal age. In adult rats (> 60days postnatal age), the effect of both purine analogues was low. Roscovitine even at 200 μM concentration did not inhibit the fraction of DNA synthesis insensitive to hydroxyurea (unscheduled DNA synthesis (UDS)). In addition, in the RG2 rat glioma model, roscovitine produced a strong inhibition of DNA synthesis in glioma cells when compared to adult normal tissue. Since in adult rat brain more than 60% of DNA synthesis is related to DNA repair, usually measured as UDS, our results indicate that roscovitine strongly blocks ongoing DNA synthesis connected with replicative processes. KeywordsScheduled unscheduled DNA synthesis-Roscovitine-Olomoucine-Purines-Cerebral cortex-Glioma-RG2 model
  Investigational New Drugs 04/2012; 28(3):299-305.
• Article: Mixed steroidal tetraoxanes induce apoptotic cell death in tumor cells

  Željko Žižak, Zorica Juranić, Dejan Opsenica, Bogdan A. Šolaja
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  ABSTRACT: In this study we investigated the antiproliferative activity of six mixed steroidal tetraoxanes against various tumor cell lines, the toxicity against normal peripheral blood mononuclear cells (PBMC), and the mode of HeLa cell death induced by these compounds. Investigated tetraoxanes exerted a dose dependent antiproliferative action at micromolar concentrations toward target tumor cell lines. Treatment of HeLa cells for 24h with all tetraoxanes induced apoptosis, as confirmed by morphological analysis and by the appearance of a typical ladder pattern in the DNA fragmentation assay.
  Investigational New Drugs 04/2012; 27(5):432-439.
• Article: Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by a new series of substituted-1,3,4-oxadiazole derivatives

  Akhilesh Kumar, Saritha S. D’Souza, S. L. Gaonkar, K. M. L. Rai, Bharathi P. Salimath
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  ABSTRACT: The multiple pharmacological actions of unique synthetic compounds are a prerequisite for classifying a drug as highly efficacious, because the multiple pharmacological actions offer the possibility of treating various diseases like cancer. 1,3,4-Oxadiazoles are an important class of heterocyclic compounds with broad spectrum of biological activities. In this study we focused on the ability of these derivatives to induce apoptosis in cultured MCF-7 breast cancer cells. Treatment of MCF-7 cells with varying concentrations of the different derivatives resulted in dose and time dependent sequence of events marked by apoptosis, as shown by loss of cell viability, chromatin condensation, internucleosomal DNA fragmentation and sub G0 phase accumulation. Furthermore, apoptosis in MCF-7 cell was induced by upregulation of proto-oncoprotein Bax and activation of Caspase-3 activated DNase. Although the derivatives induced apoptosis was associated with Bax protein levels, negligible Bcl-2 reduction was observed. Analysis of the data suggests that the substituted oxadiazole derivatives exert antiproliferative action and growth inhibition on MCF-7 cells through apoptosis induction and that it may have anticancer properties valuable for application in drug products.
  Investigational New Drugs 04/2012; 26(5):425-435.
• Article: Synthesis and in vitro cytotoxic evaluation of novel diazaspiro bicyclo hydantoin derivatives in human leukemia cells: A SAR study

  C. S. Ananda Kumar, C. V. Kavitha, K. Vinaya, S. B. Benaka Prasad, N. R. Thimmegowda, S. Chandrappa, Sathees C. Raghavan, K. S. Rangappa
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  ABSTRACT: To study the structure activity relationship (SAR) on the cytotoxic activity and probe the structural requirement for the potent antitumor activity, a series of novel diazaspiro bicyclo hydantoin derivatives were designed and synthesized. Their structures were confirmed by 1H NMR, LCMS and IR analyses. The antiproliferative effect of these compounds were determined against human leukemia, K562 (chronic myelogenous leukemia) and CEM (T-cell leukemia) cells using trypan blue and MTT assay, and the SAR associated with the position of N-terminal substituents in diazaspiro bicyclo hydantoin have also been discussed. It has been observed that these compounds displayed strong, moderate and weak cytotoxic activities. Interestingly, compounds having electron withdrawing groups at third and fourth position of the phenyl ring displayed selectively cytotoxic activities to both the cell lines tested with IC50 value lower than 50μM. In addition, the cytotoxic activities of the compounds 7(a–o) bearing the substituents at N−3 position of diazaspiro bicyclo hydantoin increases in the order alkene > ester > ether and plays an important role in determining their antitumor activities. The position and number of substituents in benzyl group attached to N−8 of diazaspiro bicyclo hydantoin nucleus interacted selectively with specific targets leading to the difference of biochemical and pharmacological effects.
  Investigational New Drugs 04/2012; 27(4):327-337.