RESUMO
BACKGROUND: The nucleoside FF-10502-01, structurally similar to but with different biologic effects than gemcitabine, shows promising activity both alone and combined with cisplatin in preclinical gemcitabine-resistant tumor models. We conducted an open-label, single-arm, 3 + 3 first-in-human trial to explore the safety, tolerability, and antitumor activity of FF-10502-01 in patients with solid tumors. METHODS: Patients with inoperable metastatic tumors refractory to standard therapies were enrolled. Escalating intravenous FF-10502-01 doses (8-135 mg/m2 ) were administered weekly for 3 weeks in 28-day cycles until progressive disease or unacceptable toxicity was observed. Three expansion cohorts were subsequently evaluated. RESULTS: A phase 2 dose of 90 mg/m2 was determined after evaluating 40 patients. Dose-limiting toxicities included hypotension and nausea. Phase 2a enrolled patients with cholangiocarcinoma (36), gallbladder cancer (10), and pancreatic/other tumors (20). Common adverse events were grade 1-2 rash, pruritus, fever, and fatigue. Grade 3 or 4 hematologic toxicities were observed at low incidences, including thrombocytopenia (5.1%) and neutropenia (2%). Confirmed partial responses (PRs) occurred in five patients with gemcitabine-refractory tumors, including three with cholangiocarcinoma and one each with gallbladder and urothelial cancer. Median progression-free and overall survival rates in patients with cholangiocarcinoma were 24.7 and 39.1 weeks, respectively. Prolonged progression-free survival in patients with cholangiocarcinoma was associated with BAP1 and PBRM1 mutations. CONCLUSION: FF-10502-01 was well tolerated with manageable side effects and limited hematologic toxicity. Durable PRs and disease stabilizations were observed in heavily pretreated biliary tract patients who had received prior gemcitabine. FF-10502-01 is distinct from gemcitabine and may represent an effective therapy.
Assuntos
Neoplasias dos Ductos Biliares , Colangiocarcinoma , Neoplasias da Vesícula Biliar , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ductos Biliares Intra-Hepáticos , Colangiocarcinoma/tratamento farmacológico , Desoxicitidina , GencitabinaRESUMO
The novel positive-contrast magnetic resonance imaging (MRI) marker C4 consists of an aqueous solution of cobalt chloride (CoCl2) complexed with the chelator N-acetylcysteine (NAC). We evaluated whether the presence of C4 or its components would produce reactive oxygen species (ROS, including hydroxyl, peroxyl, or other reactive oxygen species) in cultured cells. Human cancer or normal cells were incubated with 1% (w/v) CoCl2·6H2O or 2% NAC or a combination of both (1% CoCl2·6H2O : 2% NAC in an aqueous solution, abbreviated as Co : NAC) in the presence or absence of H2O2. Intracellular ROS levels were measured and quantified by change in relative fluorescence units. Student's t-tests were used. In all cell lines exposed to 1000 µM H2O2, the Co : NAC led to ≥94.7% suppression of ROS at 5 minutes and completely suppressed ROS at 60 and 90 minutes; NAC suppressed ROS by ≥76.6% at 5 minutes and by ≥94.5% at 90 minutes; and CoCl2·6H2O suppressed ROS by ≥37.2% at 30 minutes and by ≥48.6% at 90 minutes. These results demonstrate that neither Co : NAC nor its components generated ROS; rather, they suppressed ROS production in cultured cells, suggesting that C4 would not enhance ROS production in clinical use.
RESUMO
PURPOSE: C4, a cobalt dichloride-N-acetyl cysteine complex, is being developed as a positive-signal magnetic resonance imaging (MRI) marker to localize implanted radioactive seeds in prostate brachytherapy. We evaluated the toxicity and biodistribution of C4 in rats with the goal of simulating the systemic effects of potential leakage from C4 MRI markers within the prostate. METHODS AND MATERIALS: 9-µL doses (equivalent to leakage from 120 markers in a human) of control solution (0.9% sodium chloride), 1% (proposed for clinical use), and 10% C4 solution were injected into the prostates of male Sprague-Dawley rats via laparotomy. Organ toxicity and cobalt disposition in plasma, tissues, feces, and urine were evaluated. RESULTS: No C4-related morbidity or mortality was observed in the biodistribution arm (60 rats). Biodistribution was measurable after 10% C4 injection: cobalt was cleared rapidly from periprostatic tissue; mean concentrations in prostate were 163 µg/g and 268 µg/g at 5 and 30 minutes but were undetectable by 60 minutes. Expected dual renal-hepatic elimination was observed, with percentages of injected dose recovered in tissues of 39.0 ± 5.6% (liver), >11.8 ± 6.5% (prostate), and >5.3 ± 0.9% (kidney), with low plasma concentrations detected up to 1 hour (1.40 µg/mL at 5-60 minutes). Excretion in urine was 13.1 ± 4.6%, with 3.1 ± 0.54% recovered in feces by 24 hours. In the toxicity arm, 3 animals died in the control group and 1 each in the 1% and 10% groups from surgical or anesthesia-related complications; all others survived to scheduled termination at 14 days. No C4-related adverse clinical signs or organ toxicity were observed. CONCLUSION: C4-related toxicity was not observed at exposures at least 10-fold the exposure proposed for use in humans. These data demonstrating lack of systemic toxicity with dual routes of elimination in the event of in situ rupture suggest that C4 warrants further investigation as an MRI marker for prostate brachytherapy.
Assuntos
Acetilcisteína/análogos & derivados , Acetilcisteína/farmacocinética , Imageamento por Ressonância Magnética/métodos , Próstata/metabolismo , Acetilcisteína/toxicidade , Animais , Braquiterapia/métodos , Humanos , Rim/metabolismo , Fígado/metabolismo , Masculino , Neoplasias da Próstata/radioterapia , Ratos , Distribuição TecidualRESUMO
Erlotinib (Tarceva), an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has clinical activity in advanced lung cancer, but disease that initially responds to erlotinib eventually progresses. The mechanism of this acquired resistance is unclear. We established two erlotinib-resistant pools of A-431 cells, a well-characterized epidermoid cancer cell line that constitutively overexpresses EGFR and is sensitive to erlotinib, by continuous exposure to erlotinib over a 6-month period. The extent of EGFR gene amplification or mutation of the EGFR tyrosine kinase domain was not altered in the resistant cells. Intracellular erlotinib concentrations, determined by liquid chromatography-tandem mass spectrometry, were almost the same in all three cell lines. Immunoprecipitation with EGFR antibody followed by detection with phosphotyrosine antibody revealed that erlotinib effectively reduced EGFR phosphorylation in both parental cells and resistant cells. Erlotinib induced mutated in multiple advanced cancers 1/phosphatase and tensin homologue (MMAC1/PTEN) and suppressed phosphorylated Akt (Ser(473)) but not in the erlotinib-resistant cells. Overexpression of MMAC1/PTEN by transfection with Ad.MMAC1/PTEN or by pharmacologic suppression of Akt activity restored erlotinib sensitivity in both resistant pools. Further, transfection of parental A-431 cells with constitutively active Akt was sufficient to cause resistance to erlotinib. We propose that acquired erlotinib resistance associated with MMAC1/PTEN down-regulation and Akt activation could be overcome by inhibitors of signaling through the phosphatidylinositol 3-kinase pathway.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , PTEN Fosfo-Hidrolase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/farmacologia , Sequência de Bases , Western Blotting , Linhagem Celular Tumoral , Cromatografia Líquida , Regulação para Baixo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Cloridrato de Erlotinib , Citometria de Fluxo , Dosagem de Genes , Humanos , Imunoprecipitação , Hibridização in Situ Fluorescente , Espectrometria de Massas , Dados de Sequência Molecular , Mutação , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transfecção , Regulação para CimaRESUMO
Microdialysis sampling of blood and extracellular fluid (ECF) of living tissue offers unique advantages for studying anticancer drug distribution, metabolism, and mechanisms of tumor drug resistance. We applied microdialysis sampling in a rat model to describe the pharmacokinetics of cisplatin and carboplatin simultaneously in blood and several peripheral tissues, including tumor tissue. After i.v. bolus drug administration, samples were collected every 10 min for 4-6 h using microdialysis probes implanted into the jugular vein, kidney, and either liver or subcutaneously growing breast tumor tissue in anesthetized Fisher 344 rats. Analyte concentrations are expressed as absolute extracellular concentrations obtained by correction of the data for in vivo recovery. For cisplatin, peak renal concentrations (mean, 36.7 and 80.1 micrograms/mL) always exceeded peak plasma (8.4 and 13.2 micrograms/mL) and hepatic (6.3 and 10.4 micrograms/mL) concentrations following 5 and 10 mg/kg doses, respectively. For carboplatin, doses of 20 and 30 mg/kg also resulted in high peak renal concentrations, which were similar at both dose levels (mean, 87.9 and 89.3 micrograms/mL). However, at 30 mg/kg peak hepatic carboplatin concentrations were increased significantly, resulting in a disproportionate 3.5-fold increase in mean AUC at the higher dose level. Tumor cisplatin and carboplatin AUCs were similar to that in the circulation, but variable, ranging from 52 to 109% of the corresponding plasma AUCs. Microdialysis was determined to be a reliable methodology for examining the in vivo disposition of platinum anticancer agents in multiple tissue types. Our results revealed expected large renal exposures following i.v. administration, and variable tumor exposure with dose. Significant increases in hepatic carboplatin exposure with increasing dose suggest a possible mechanism for high-dose carboplatin-induced hepatic toxicity.