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Abstract : Metabolic Activation and Inactivation of Irinotecan when Combined with the Human Monoclonal Antibody Bevacizumab
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Abstract: Purpose: This pharmacokinetic study was designed to investigate whether the co-administration of the monoclonal antibody bevacizumab (BVC) shows potential to modulate the plasma disposition of irinotecan (CPT-11) and its metabolites. Patients and Methods: Ten patients suffering from advanced colorectal cancer entered this pharmacokinetic study. Patients received CPT-11 as a 60 min i.v. - infusion (180 mg/m2, total dose 339 ± 32 mg) weekly for six weeks. BVC was administered biweekly as an intravenous 90 min infusion containing 5 mg BVC per kg body weight in 100 ml balanced sodium chloride solution. Pre-medication consisted of tropisetrone (3 mg i.v. push) and atropine (0.5 mg i.v.) one hour before CPT-11 infusion. Plasma samples were analysed during / after the first (MONO) and after the third CPT-11 infusion (BVC regimen). Results: BVC did not alter plasma disposition and pharmacokinetics of the parent compound CPT-11, but in contrary BVC appeared to lower the plasma concentrations of the metabolites SN-38, SN-38gluc and APC. Conclusion: Overall, our findings indicate that administration of BVC prior to chemotherapy showed no clinically significant impact on the pharmacokinetics and metabolic activation of CPT-11. Keywords: CPT-11, metabolites, pharmacokinetics, bevacizumab, advanced colorectal cancer, enzymatic activation.Download Full Article |
Abstract : The Effect of Pretreatment with Chemotherapeutic Drugs on the Susceptibility to Lymphokine Activated CD8+ T Lymphocyte-Mediated Cytotoxicity in CMK Leukemia Cells
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Abstract: Objectives: Certain tumor cells pretreated with chemotherapeutic drugs become more susceptible to death by apoptosis induced by killer cells of the immune system. We examined the CD8+ cytotoxic T lymphocyte (CTL)-mediated cytotoxicity in myeloid leukemia cell lines pretreated with chemotherapeutic drugs. Methods: Peripheral blood mononuclear cells were expanded in vitro in the presence of phytohemagglutinin-P, interleukins-2 and -15. CD3+ CD8+ cells representing the CTLs were isolated using magnetic immunoselection and used in immune cytotoxicity experiments against K562 and CMK leukemia cells, pretreated with two different concentrations of cytarabine and etoposide. Results: In CMK cells pretreated with etoposide at 2 μM and 20 μM concentrations, the mean cell-mediated immune cytotoxicity rose to 21.4 ± 12.9% (p=0.09) and 23.4 ± 12.6% (p=0.046), respectively, when compared to the control value of 6.6 ± 3.8%. In CMK cells pretreated with cytarabine at 1 μM and 10 μM concentrations, the mean immune cytotoxicity rose to 14.3 ± 11.2% and 22.6 ± 15.2%, respectively, compared to the control value of 8.7 ± 6.3%, although these results did not reach statistical significance. However, a similar increase in CTL-mediated immune cytotoxicity was not observed against drug-treated K562 cells. Conclusion: This study suggests that pretreatment with chemotherapeutic drugs can render CMK leukemia cells more susceptible to immune attack by activated CTLs. Further studies are needed to explore this phenomenon, to establish an immune-enhancing effect of pretreatment with chemotherapy in the treatment of leukemia. Keywords: Leukemia, cytotoxic T lymphocytes, chemotherapy, apoptosis.Download Full Article |
Abstract : A DNA Vaccine Targeting the Fetal Liver Kinase-1 (Flk-1) can Activate the Special CD8+ T Cell and Inhibit the Metastasis of Orthotopic Lewis Lung Cancer Model
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Abstract: Lung cancer is the leading cause of cancer related deaths and need new more effective therapies. In this study, we investigated the anti-tumor effect of recombinant orally DNA vaccine delivered by attenuated S.typhimurium strain SL3261 (aroA mutant) targeting vascular endothelial growth factor receptor (VEGFR-2), also known as fetal liver kinase-1 (Flk-1) in mouse. The cDNA of extracellular domains (ECD) of VEGFR-2 (Flk-1ECD) was amplified by RT-PCR and cloned into the pcDNA3.1 (+) vector, then transformed to the attenuated S.typhimurium strain to construct the oral DNA vaccine. Then pcDNA3.1-Flk-1ECD was successfully transfected into COS-7 cells and the recombinant protein was detected by Western blot. The effect of the oral DNA vaccine was analyzed by flow cytometry (FCM) analysis and cytotoxicity assay. For mimic the local and regional growth pattern seen in lung cancer patients, the effect of the oral DNA vaccine on tumor growth and metastasis was analyzed by orthotopic cancer cells challenge in vivo. The results demonstrated that the oral DNA vaccine can overcome peripheral immune tolerance, and generated Flk-1- specific CD8+ cytotoxic T cell response. Moreover, this oral DNA vaccine could effectively reduce tumor growth, metastasis and increase the survival. It indicated that the oral VEGFR2 DNA vaccine encoding Flk-1ECD delivered by salmonella might act a potential strategy for immunotherapy of lung cancers. Keywords: Lung cancer, VEGFR-2, oral vaccine, angiogenesis, metastasis, orthotopic.Download Full Article |
Abstract : Bevacizumab Plus Chemotherapy as First-Line Treatment for Patients with Metastatic Colorectal Cancer: Results from a Spanish Observational Study
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Abstract: Background: This observational study evaluated the efficacy and safety of treatment with bevacizumab plus chemotherapy until disease progression (PD) in Spanish patients with metastatic colorectal cancer (mCRC). Methods: This multicentre, retrospective, observational analysis included patients receiving bevacizumab plus fluoropyrimidine-based chemotherapy as first-line treatment for mCRC who then developed PD. All patients received treatment in hospital oncology departments and none received bevacizumab as part of a clinical trial. Patients discontinuing treatment with bevacizumab for reasons other than PD were excluded. The primary endpoint was PFS; secondary endpoints were overall response rate (ORR) and safety. Results: Overall, 165 patients were evaluable for analysis: median age 63.0 years; male/female 62%/38%; ECOG performance status 0/1/2 55%/43%/2%. Median duration of bevacizumab treatment was 8.7 months. ORR was 48.5% (6 complete and 74 partial responses) and disease control rate was 74%. Median progression-free survival (PFS) was 8.4 months (95% CI 7.2–9.6). Patients receiving oxaliplatin- or irinotecan-based regimens had median PFS of 9.2 and 7.7 months, respectively; those receiving treatment not containing either oxaliplatin or irinotecan had a median PFS of 6.1 months. KRAS status did not have a statistically significant effect on PFS (9.5 vs. 7.8 months for KRAS wild-type vs. mutant tumours, respectively; p=0.647) or ORR (44.8% vs. 52.6%, respectively; p=0.391). The most common grade 3/4 adverse events were: diarrhoea (7%), paraesthesia (7%), neutropenia (3%), cutaneous toxicity (2%), and thrombocytopenia (2%). Conclusions: Treatment with bevacizumab plus standard chemotherapy is an effective and well-tolerated option for patients with mCRC who continue treatment until PD. Keywords: Bevacizumab, mCRC, observational, clinical practice, disease progression.Download Full Article |
