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1.
Ann Oncol ; 31(5): 619-625, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32205016

RESUMO

BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas , Humanos , Masculino , Nitrilas , Feniltioidantoína/análogos & derivados , Fosfatidilinositol 3-Quinases , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt , Pirimidinas , Pirróis , Resultado do Tratamento
2.
Ann Oncol ; 29(9): 1918-1925, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30016392

RESUMO

Background: We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods: In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results: The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25). Discussion: In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration: ClinicialTrials.gov identifier: CNCT02193633.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzamidas/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/patologia , Morfolinas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/patologia , Esquema de Medicação , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Dose Máxima Tolerável , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 2 de Rapamicina/antagonistas & inibidores , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/efeitos adversos , Pirimidinas/farmacocinética , Critérios de Avaliação de Resposta em Tumores Sólidos , Proteínas Quinases S6 Ribossômicas/metabolismo
3.
Leukemia ; 26(7): 1462-70, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22354205

RESUMO

Acquired resistance to selective FLT3 inhibitors is an emerging clinical problem in the treatment of FLT3-ITD(+) acute myeloid leukaemia (AML). The paucity of valid pre-clinical models has restricted investigations to determine the mechanism of acquired therapeutic resistance, thereby limiting the development of effective treatments. We generated selective FLT3 inhibitor-resistant cells by treating the FLT3-ITD(+) human AML cell line MOLM-13 in vitro with the FLT3-selective inhibitor MLN518, and validated the resistant phenotype in vivo and in vitro. The resistant cells, MOLM-13-RES, harboured a new D835Y tyrosine kinase domain (TKD) mutation on the FLT3-ITD(+) allele. Acquired TKD mutations, including D835Y, have recently been identified in FLT3-ITD(+) patients relapsing after treatment with the novel FLT3 inhibitor, AC220. Consistent with this clinical pattern of resistance, MOLM-13-RES cells displayed high relative resistance to AC220 and Sorafenib. Furthermore, treatment of MOLM-13-RES cells with AC220 lead to loss of the FLT3 wild-type allele and the duplication of the FLT3-ITD-D835Y allele. Our FLT3-Aurora kinase inhibitor, CCT137690, successfully inhibited growth of FLT3-ITD-D835Y cells in vitro and in vivo, suggesting that dual FLT3-Aurora inhibition may overcome selective FLT3 inhibitor resistance, in part due to inhibition of Aurora kinase, and may benefit patients with FLT3-mutated AML.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , Sequências de Repetição em Tandem/genética , Tirosina Quinase 3 Semelhante a fms/genética , Animais , Apoptose/efeitos dos fármacos , Aurora Quinases , Benzenossulfonatos/farmacologia , Benzotiazóis/farmacologia , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Imidazóis/farmacologia , Camundongos , Camundongos Nus , Niacinamida/análogos & derivados , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Piridinas/farmacologia , Quinazolinas/farmacologia , Sorafenibe , Células Tumorais Cultivadas , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/metabolismo
4.
Curr Med Chem ; 18(18): 2686-714, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21649578

RESUMO

The phosphoinositide 3-kinases (PI3Ks) constitute an important family of lipid kinase enzymes that control a range of cellular processes through their regulation of a network of signal transduction pathways, and have emerged as important therapeutic targets in the context of cancer, inflammation and cardiovascular diseases. Since the mid-late 1990s, considerable progress has been made in the discovery and development of small molecule ATP-competitive PI3K inhibitors, a number of which have entered early phase human trials over recent years from which key clinical results are now being disclosed. This review summarizes progress made to date, primarily on the discovery and characterization of class I and dual class I/IV subtype inhibitors, together with advances that have been made in translational and clinical research, notably in cancer.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Medicina Clínica/métodos , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Doenças Cardiovasculares/enzimologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Medicina Clínica/tendências , Humanos , Inflamação/enzimologia , Neoplasias/enzimologia , Inibidores de Proteínas Quinases/farmacologia
5.
Br J Cancer ; 101(11): 1860-8, 2009 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-19935799

RESUMO

BACKGROUND: SR4554 is a fluorine-containing 2-nitroimidazole, designed as a hypoxia marker detectable with 19F magnetic resonance spectroscopy (MRS). In an initial phase I study of SR4554, nausea/vomiting was found to be dose-limiting, and 1400 mg m(-2) was established as MTD. Preliminary MRS studies demonstrated some evidence of 19F retention in tumour. In this study we investigated higher doses of SR4554 and intratumoral localisation of the 19F MRS signal. METHODS: Patients had tumours > or = 3 cm in diameter and < or = 4 cm deep. Measurements were performed using 1H/19F surface coils and localised 19F MRS acquisition. SR4554 was administered at 1400 mg m(-2), with subsequent increase to 2600 mg m(-2) using prophylactic metoclopramide. Spectra were obtained immediately post infusion (MRS no. 1), at 16 h (MRS no. 2) and 20 h (MRS no. 3), based on the SR4554 half-life of 3.5 h determined from a previous study. 19Fluorine retention index (%) was defined as (MRS no. 2/MRS no. 1)*100. RESULTS: A total of 26 patients enrolled at: 1400 (n=16), 1800 (n=1), 2200 (n=1) and 2600 mg m(-2) (n=8). SR4554 was well tolerated and toxicities were all < or = grade 1; mean plasma elimination half-life was 3.7+/-0.9 h. SR4554 signal was seen on both unlocalised and localised MRS no. 1 in all patients. Localised 19F signals were detected at MRS no. 2 in 5 out of 9 patients and 4 out of 5 patients at MRS no. 3. The mean retention index in tumour was 13.6 (range 0.6-43.7) compared with 4.1 (range 0.6-7.3) for plasma samples taken at the same times (P=0.001) suggesting (19)F retention in tumour and, therefore, the presence of hypoxia. CONCLUSION: We have demonstrated the feasibility of using 19F MRS with SR4554 as a potential method of detecting hypoxia. Certain patients showed evidence of 19F retention in tumour, supporting further development of this technique for detection of tumour hypoxia.


Assuntos
Espectroscopia de Ressonância Magnética/métodos , Neoplasias/metabolismo , Nitroimidazóis/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Hipóxia Celular/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nitroimidazóis/efeitos adversos , Oxigênio/metabolismo , Pressão Parcial , Adulto Jovem
6.
J Chromatogr B Analyt Technol Biomed Life Sci ; 877(13): 1352-8, 2009 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-19101213

RESUMO

The reproducibility of a metabolomics method has been assessed to identify changes in tumour cell metabolites. Tissue culture media extracts were analyzed by reverse phase chromatography on a Waters Acquity T3 column with a 13 min 0.1% formic acid: acetonitrile gradient on Agilent and Waters LC-Q-TOF instruments. Features (m/z, RT) were extracted by MarkerLynx (Waters) and Molecular Feature Extractor (Agilent) in positive and negative ionization modes. The number of features were similar on both instruments and the reproducibility of ten replicates was <35% signal variability for approximately 50% and 40% of all ions detected in positive and negative ionization modes, respectively. External standards spiked to the matrix showed CVs <25% in peak areas within and between days. U87MG glioblastoma cells exposed to the PI 3-Kinase inhibitor LY294002 showed significant alterations of several confirmed features. These included glycerophosphocholine, already shown by NMR to be modulated by LY294002, highlighting the power of this technology for biomarker discovery.


Assuntos
Neoplasias Encefálicas/metabolismo , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Glioblastoma/metabolismo , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/patologia , Humanos , Reprodutibilidade dos Testes
7.
Br J Cancer ; 93(9): 1011-8, 2005 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-16249792

RESUMO

In this study we investigated the in vitro time dependence of radiosensitisation, pharmacokinetics and metabolism of NU7026, a novel inhibitor of the DNA repair enzyme DNA-dependent protein kinase (DNA-PK). At a dose of 10 muM, which is nontoxic to cells per se, a minimum NU7026 exposure of 4 h in combination with 3 Gy radiation is required for a significant radiosensitisation effect in CH1 human ovarian cancer cells. Following intravenous administration to mice at 5 mg kg(-1), NU7026 underwent rapid plasma clearance (0.108 l h(-1)) and this was largely attributed to extensive metabolism. Bioavailability following interperitoneal (i.p.) and p.o. administration at 20 mg kg(-1) was 20 and 15%, respectively. Investigation of NU7026 metabolism profiles in plasma and urine indicated that the compound undergoes multiple hydroxylations. A glucuronide conjugate of a bis-hydroxylated metabolite represented the major excretion product in urine. Identification of the major oxidation site as C-2 of the morpholine ring was confirmed by the fact that the plasma clearance of NU7107 (an analogue of NU7026 methylated at C-2 and C-6 of the morpholine ring) was four-fold slower than that of NU7026. The pharmacokinetic simulations performed predict that NU7026 will have to be administered four times per day at 100 mg kg(-1) i.p. in order to obtain the drug exposure required for radiosensitisation.


Assuntos
Cromonas/metabolismo , Cromonas/farmacocinética , Proteína Quinase Ativada por DNA/antagonistas & inibidores , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacocinética , Morfolinas/metabolismo , Morfolinas/farmacocinética , Neoplasias Ovarianas/metabolismo , Animais , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Avaliação Pré-Clínica de Medicamentos , Feminino , Raios gama , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Ovarianas/radioterapia , Tolerância a Radiação , Ensaio Tumoral de Célula-Tronco
8.
Cancer Chemother Pharmacol ; 54(6): 475-86, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15526201

RESUMO

PURPOSE: There is currently much interest in developing analogues of the benzoquinone ansamycin geldanamycin that may overcome the limitations of 17-(allylamino)-17-demethoxygeldanamycin (17AAG), which is the first known inhibitor of heat shock protein 90 (Hsp90) to enter clinical trials. Studies were performed to assess whether cassette dosing, the coadministration of several compounds to a single animal, is a suitable approach to evaluate the preclinical pharmacokinetics of geldanamycin analogues in high throughput. METHODS: Five geldanamycin analogues (17AAG, NSC 255110, NSC 682300, NSC 683661, NSC 683663) were administered intravenously to mice in combination at 5 mg/kg each and as single agents at 5 mg/kg and 50 mg/kg, or 12.5 mg/kg for NSC 682300. The compounds were also incubated with mouse liver microsomes individually and in combination at 15 microM each. Quantitative analysis was performed by LC/MS/MS. Plasma and tissue pharmacokinetic parameters were evaluated by non-compartmental analysis. In vitro metabolic stability was assessed by monitoring disappearance of the parent compound. RESULTS: Of the compounds that were detectable following individual administration at 5 mg/kg, 17AAG and NSC 683661 exhibited nonlinear pharmacokinetics. In addition, the plasma area under the curve (AUC) and the half-life of these compounds was greater following cassette dosing at 5 mg/kg compared to single administration at the same dose. When pharmacokinetic parameters were calculated up to the same time point following cassette and individual administration at the higher dose, three of the compounds displayed non-linear increases in AUC and slower clearances following cassette compared to single compound dosing. When all measurable concentrations at the higher dose were included, the half-life of NSC 683663 was nine-fold longer following individual compared to cassette administration. 17AAG displayed the highest AUC following cassette dosing, whereas NSC 683663 displayed the highest AUC following single-compound dosing. Excluding NSC 683663, the rank order from the highest to the lowest AUC was the same; however, NSC 682300, which ranked fifth, was administered at a four-fold lower individual dose than the other compounds. Exposure of the liver and kidneys to the compounds was greater than that of plasma. Despite being administered at a lower dose, NSC 682300 displayed the highest kidney AUC of the five compounds. The same ranking was maintained between cassette and single compound dosing in the kidney. With the exception of NSC 682300, in vitro metabolic stability was predictive of in vivo pharmacokinetics in the plasma and liver. The extent of metabolism of four of the five compounds was lower following microsomal incubation in combination compared to incubation alone, suggestive of likely drug-drug interaction in the cassette. However, for 17AAG this may be partly due to metabolism of NSC 683661 and NSC 683663 to this compound. CONCLUSIONS: Whilst cassette dosing has advantages for use in drug discovery, it is probably unsuitable to evaluate the pharmacokinetics of geldanamycin analogues due to non-linear pharmacokinetics and drug-drug interaction. The issues identified for this compound series should also be considered in assessing the suitability of cassette dosing for other chemotypes.


Assuntos
Sistemas de Liberação de Medicamentos , Quinonas/administração & dosagem , Quinonas/farmacocinética , Animais , Benzoquinonas , Quimioterapia Combinada , Meia-Vida , Técnicas In Vitro , Lactamas Macrocíclicas , Camundongos , Microssomos Hepáticos/metabolismo , Distribuição Tecidual
9.
J Inorg Biochem ; 77(1-2): 111-5, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10626362

RESUMO

The discovery and development of new platinum-containing anticancer drugs have represented an integral part of anticancer drug development at the Institute of Cancer Research, Sutton, over almost 20 years. As part of a collaboration with chemists at Johnson Matthey, later AnorMED, four major new classes of platinum drug have been discovered, three of which have entered clinical trial. Earlier studies led to the clinical development of the less toxic analogue carboplatin and JM216, the first orally administerable platinum drug. In recent years, the focus has been on two lead complexes designed to overcome the major mechanisms of tumour resistance to cisplatin: JM335 (trans-ammine (cyclohexylaminedichlorodihydroxo) platinum(IV)), an active trans platinum complex; and ZD0473 (cis-amminedichloro(2-methylpyridine) platinum(II)), a sterically hindered complex shown to be less reactive towards thiol-containing molecules than cisplatin. JM335 shows some circumvention of acquired cisplatin resistance in vitro and exhibits unique cellular pharmacological properties in comparison to cisplatin or its cis-isomer in terms gene-specific repair of adducts on DNA and the rate of induction of apoptosis. ZD0473 is now in phase I clinical trial. Myelosuppression is the dose-limiting toxicity at a dose of 130 mg/m2 given i.v. every 3 weeks and there has been evidence of antitumour activity. ZD0473-resistant human ovarian carcinoma cell lines have been established in vitro. Some mechanisms of resistance common to those described for cisplatin (decreased drug uptake, increased glutathione) have been observed plus, in one cell line, increased BCL2 levels and loss of the DNA mismatch repair protein MLH1.


Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Compostos de Platina/química , Compostos de Platina/farmacologia , Antineoplásicos/química , Desenho de Fármacos , Humanos , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacologia , Células Tumorais Cultivadas
10.
J Pharmacol Exp Ther ; 281(1): 420-7, 1997 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-9103525

RESUMO

An 18-mer full-phosphorothioate oligonucleotide with sequence antisense to the first six codons of the open reading frame of bcl-2 (G3139) has shown efficacy against the DoHH2 lymphoma implanted in severe combined immunodeficient mice. This study evaluated the pharmacokinetics of 35S-labeled G3139 in female BALB/c mice after single i.v. bolus administration or s.c. infusion for 1 week. After 100 microg i.v. bolus (approximately 5 mg/kg), the radioactivity was rapidly distributed and eliminated, with low blood levels 6 hr after administration. Most of the initial plasma radioactivity was protein bound (98% at 5 min). Tissue to plasma ratios were 87 for kidney, 17 for liver, 5 for spleen, 2.5 for heart and lung and 3.5 for gut. High-performance liquid chromatographic determination of G3139 showed triexponential kinetics, with alpha, beta and gamma half-lives of 5 min, 37 min and 11 hr, respectively. After 106 microg/day s.c. infusion, plasma steady state was reached by day 3, when half of the radioactivity was protein bound and 66 to 86% of the radioactivity was associated with parent drug (0.9 microg/ml). The plasma half-life of elimination for G3139 was 22 hr. Tissue to plasma ratios were similar to those after i.v. bolus administration, but accumulation was observed in all organs including bone marrow, where the levels reached were in the cytotoxic range. G3139 was metabolized to at least three different products, all observed in plasma, liver and kidney. Two metabolites eluted before the parent compound and one after the parent compound. There was greater degradation in the liver 6 hr after i.v. administration than at 24 hr, 48 hr, 3 days and 7 days after s.c. administration. In the kidney, most radioactivity was G3139. All degradation products were found in the urine but only traces of parent drug were eliminated. After both routes of administration, most of the radioactivity was eliminated in the urine and to a lesser extent in the feces. Significantly more radioactivity was excreted in the urine after i.v. bolus, compared with s.c. infusion (33% on day 1 and 55% by day 3 for i.v. vs. 7.2% on day 1 and 12.9% by day 3 for s.c.). These data show that s.c. infusion resulted in less excretion and metabolism of the administered dose.


Assuntos
Genes bcl-2 , Oligonucleotídeos Antissenso/farmacocinética , Tionucleotídeos/farmacocinética , Animais , Feminino , Injeções Intravenosas , Camundongos , Camundongos Endogâmicos BALB C , Oligonucleotídeos Antissenso/administração & dosagem , Distribuição Tecidual
11.
Sarcoma ; 1(3-4): 149-54, 1997.
Artigo em Inglês | MEDLINE | ID: mdl-18521217

RESUMO

Purpose. The study was performed to assess the antitumour activity and toxicity of a 72-h continuous infusion of single-agent etoposide as second-line treatment for patients with locally advanced or metastatic soft tissue sarcoma (STS), following reports of substantial activity using this schedule of etoposide administration as first-line treatment in combination with ifosfamide.Patients/method. This was an open phase I/II trial performed at a single institution in patients with metastatic or locally advanced STS who had failed first-line treatment with doxorubicin + ifosfamide combination chemotherapy or, less commonly, single-agent treatment with doxorubicin or ifosfamide. Etoposide was given as a continuous intravenous infusion over 72 h. The starting dose level was 200 mg m(-2) day(-1) x 3 escalating in 10% steps in cohorts of three patients until dose-limiting toxicity was encountered.Results. Seventeen patients were treated, median age 47 years (range 26-71 years). No responses were seen in 16 assessable patients despite etoposide levels in the cotoxic range. The steady-state plasma concentration exceeded 8 mug ml-(1) in all patients and in patients treated at >/= 600 mg m -(2) the mean steady-state level was 14.4 mug ml -(1). The median event-free survival was 6 weeks (95% confidence interval (CI) 3.31-8.69) and the overall survival 16 weeks (95% CI 9.28-22.72). The maximum tolerated dose in this pretreated patient group was 200 mg mm(-2) day(-1) x 3. The dose-limiting toxicity was myelosuppression.Discussion. Etoposide given by 72-h infusion is inactive as second-line chemotherapy in STS. It is associated with significant toxicity when given in these doses, in this patient group.

12.
Clin Cancer Res ; 3(11): 2063-74, 1997 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9815598

RESUMO

A novel sterically hindered platinum complex, AMD473 [cis-amminedichloro(2-methylpyridine) platinum(II)], designed primarily to be less susceptible to inactivation by thiols, has shown in vitro activity against several ovarian carcinoma cell lines. Notably, AMD473 has shown activity in vitro in human carcinoma cells that have acquired cisplatin resistance due to reduced drug transport (41M/41McisR) or enhanced DNA repair/increased tolerance of platinum-DNA adducts (CH1/CH1cisR). In this study, we show that AMD473, at its maximum tolerated dose of 35-40 mg/kg i.p. administration, produced marked in vivo antitumor activity against a variety of murine (ADJ/PC6 plasmacytoma, L1210 leukemia) and human ovarian carcinoma xenograft models, including several possessing acquired resistance to cisplatin [ADJ/PC6cisR, L1210cisR, CH1cisR, and HX110 (carboplatin-resistant)]. In the ADJ/PC6 model, an increased therapeutic index was noted following oral as opposed to i. p. administration. In a head-to-head comparison using CH1cisR xenografts and equitoxic doses (q7dx4 schedule), comparative growth delays were as follows: AMD473, 34 days; cisplatin, 10.4 days; carboplatin, 6.4 days; and JM216 (p.o. administration), 3.5 days (in a previous experiment, the trans-platinum complex JM335 induced a growth delay of 5.4 days against this model). In this model, oral activity was also noted with a growth delay of 34 days at 400 mg/kg every 7 days (total of four doses). In addition, AMD473 showed promising activity against CH1 xenografts that had regrown following initial treatment with cisplatin (additional growth delay of 30 days over that observed for retreatment with cisplatin). Across the whole panel of cisplatin-sensitive to cisplatin-resistant human ovarian carcinoma xenografts, AMD473 showed improved or at least comparable activity to that observed for an equitoxic dose (4 mg/kg) and schedule of cisplatin. Platinum pharmacokinetics showed that following i.v. administration of 20 mg/kg AMD473 in saline to Balb/c- mice bearing murine plasmacytoma (ADJ/PC6), a biexponential decay was observed in the plasma with a rapid distribution t1/2alpha of 24 min followed by a slow elimination t1/2beta of 44 h. Platinum accumulated in various organs with platinum tissue to plasma area under the curve ratios of 8.6 for liver and kidney, 5.7 for spleen, 3.7 for heart, 5.2 for lung, and 5 for tumor. The plasma and tissue concentration time curve following i.p. administration was similar to that observed following i.v. administration, with a bioavailability of 89%. When AMD473 was given p.o., the platinum absorption was rapid (K01 of 30 min) and the bioavailability was 40%. A less than proportional increase in area under the curve and Cmax was noted in tissue, plasma, and plasma ultrafiltrate following increasing oral doses of AMD473. In vitro, with AMD473, the rate of binding to different plasma proteins was approximately half of that of cisplatin. Following administration of 45 mg/kg i.p. in oil, 33% of the administered platinum was eliminated in the urine after 24 h, and 40% was eliminated after 72 h. Fecal recovery represented 13% of the administered dose after 3 days. Similar results were observed following oral and i.v. administration of 20 mg/kg, but significantly more was excreted in the feces (over 50% of the administered dose) following oral administration of 400 mg/kg, showing that absorption might be a limiting factor by this route of administration. The dose-limiting toxicity for AMD473 in mice was myelosuppression, and no renal toxicity was observed. The promising antitumor activity of AMD473, together with its lack of nephrotoxicity and favorable pharmacokinetic profile, suggests that AMD473 is a good candidate for clinical development. AMD473 is entering Phase I clinical trials under the auspices of the United Kingdom Cancer Research Campaign in 1997.


Assuntos
Antineoplásicos/uso terapêutico , Leucemia L1210/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Plasmocitoma/tratamento farmacológico , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Carboplatina/toxicidade , Cisplatino/toxicidade , Resistencia a Medicamentos Antineoplásicos , Feminino , Meia-Vida , Humanos , Cinética , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Compostos Organoplatínicos/farmacocinética , Compostos Organoplatínicos/toxicidade , Distribuição Tecidual , Transplante Heterólogo , Células Tumorais Cultivadas
13.
Br J Cancer ; 74(3): 380-6, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-8695352

RESUMO

JM216 (bis-acetato ammine dichloro cyclohexylamine Pt IV) is an oral platinum complex presently undergoing phase II clinical trials. Previous studies have identified some of its biotransformation products in clinical materials. This study evaluated the nature of JM216 biotransformation products intracellularly in two different human ovarian carcinoma cell lines, one relatively sensitive to platinum agents (CH1: JM216 4 h IC50 of 5.8 microM) and the other relatively resistant (SKOV3: JM216 4 h IC50 of 60.7 microM). Metabolic profiles were also evaluated at different growth status and in cells pretreated with buthionine sulphoximine (BSO), an agent known to decrease intracellular glutathione levels. Results showed that JM216 enters the cells and that the nature and percentage of biotransformation products was dependent upon glutathione levels. Furthermore, results support the view that the previously reported peak A biotransformation product contains a glutathione adduct. In exponentially growing SKOV3 cells which contain higher glutathione levels than CH1, (82.5 vs 37.8 nmol mg-1 protein), peak A represented 89% of total platinum 4 h after JM216 exposure compared with only 24% in CH1. Moreover, 60-70% depletion of glutathione achieved by 24 h pretreatment of cells with BSO resulted in a significant decrease in peak A in both cell lines and increased the cytotoxicity of JM216 in both CH1 and SKOV3 by approximately 2-fold. Following a 4 h exposure of exponentially growing SKOV3 cells to JM216, only peak A (89%) and JM216 (11%) could be detected whereas in CH1 cells, peak A (24%), JM216 (73%) and JM118 [cis-ammine dichloro (cyclohexylamine) platinum II] (3%) were detected. However, in CH1 cells at confluence, where glutathione is lower (8 nmol mg-1 protein) four metabolites (plus JM216 itself) were detected following exposure to 50 microM JM216; peak A, JM118, JM383 (bis-acetato ammine (cyclohexylamine) dihydroxy platinum IV) and an unidentified metabolite (D), also observed in patient's plasma ultrafiltrate. In confluent SKOV3 cells exposed to 50 microM JM216, peak A, JM216 and JM118 were detected. A further unidentified metabolite observed in patients receiving JM216 (metabolite F) was not formed inside these tumour cells. Overall, these data suggest that glutathione conjugation represents a major deactivation pathway for JM216.


Assuntos
Antineoplásicos/metabolismo , Glutationa/metabolismo , Compostos Organoplatínicos/metabolismo , Administração Oral , Feminino , Humanos , Compostos Organoplatínicos/farmacologia , Células Tumorais Cultivadas
14.
Anticancer Res ; 16(4A): 1857-62, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8712713

RESUMO

This study evaluates the metabolism of the oral platinum drug JM216 [bis(acetato) amminedichloro (cyclohexylamine)platinum (IV)] following oral administration to Balb C- mice. JM216 was detectable 1 h post administration in mice but not in patients. Also, a late eluting metabolite observed in patients was not detected in mice. JM118 [amminedichloro(cyclohexylamine) platinum (II)], the platinum II species which is the major metabolite in patients was rapidly converted following i.v. administration to a compound having the same retention time as JM383 [bis(acetato)ammine(cyclohexylamine)dihydroxo platinum(IV)] indicating that the levels of JM383 following JM216 administration have probably been overestimated. The metabolite D observed in patients for which a structure has not been assigned, was also detected in mice. However, it did not originate from any of the identified biotransformation products. The protein binding evaluated in plasma, and buffer with physiological levels of albumin and globulin showed that only Platinum (II) species have significant binding and that Jm118 showed the same affinity to albumin and globulin (t 1/2 of 4.2 and 4.8 h) while cisplatin bound more readily to albumin (t 1/2 3.4 h) than globulin IV (t 1/2 8.2 h). JM216 itself failed to bind to either of the proteins tested indicating extensive reduction in patients, animals or plasma incubation medium. JM118 and JM518 [bis(acetato)amminechloro(cyclohexylamine) hydroxoplatinum (IV)] were significantly more active than the platinum IV complexes JM216 and JM383 when given i.p. to ADJ/PC6 plasmacytoma bearing mice (ED90 of 1.0 and 0.4 versus 5.7 and 4.2 mg/kg, TI (therapeutic index) of 14 and 37 versus 5.3 and 4.2). When given orally, JM216 was the most potent drug (ED90 of 5.8 versus 11,12 and 42 mg/kg and TI of 57 versus 12 12 and 16) for JM118 and JM383. There data indicates that JM216 biotransformation products are potent but that the levels of JM383 determined in our analytical conditions could have been overestimated.


Assuntos
Antineoplásicos/metabolismo , Antineoplásicos/uso terapêutico , Proteínas Sanguíneas/metabolismo , Compostos Organoplatínicos/metabolismo , Compostos Organoplatínicos/uso terapêutico , Plasmocitoma/tratamento farmacológico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Biotransformação , Cromatografia Líquida de Alta Pressão , Cisplatino/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Estrutura Molecular , Compostos Organoplatínicos/administração & dosagem , Ligação Proteica , Albumina Sérica/metabolismo , Soroglobulinas/metabolismo , Relação Estrutura-Atividade
15.
Cancer Chemother Pharmacol ; 38(2): 155-62, 1996.
Artigo em Inglês | MEDLINE | ID: mdl-8616906

RESUMO

This study evaluates the metabolic profile of JM216 [bis(acetato)ammine-dichloro(cyclohexylamine) platinum(IV)], the first orally administrable platinum complex, in plasma ultrafiltrates of 12 patients (n = 2-4 time points per patient) following different doses of drug (120, 200, 340, 420, 560 mg/m2). The biotransformation profile was evaluated by high-performance liquid chromatography (HPLC) followed by atomic absorption spectrophotometry (AA). The AA profiles were compared with those previously identified by HPLC on line with mass spectrometry (HPLC-MS) in plasma incubated with JM216. A total of six platinum peaks (Rt = 5.5, 7.2, 10.6, 12.4, 15.6, and 21.6 min, respectively) were observed in patients' plasma ultrafiltrate samples, of which only four appeared during the first 6 h post-treatment. Four of these coeluted with those observed and identified previously in plasma incubation medium. No parent JM216 was detected. The major metabolite seen in patients was the Pt II complex JM118 [cis-amminedichloro-(cyclohexylamine)platinum(II)] and was observed in all the patients. Interestingly, the second metabolite was shown to coelute with the Pt IV species JM383 [bis-acetatoammine(cyclohexylamine)dihydroxoplatinum (IV)]. Both JM118 and JM383 were identified by HPLC-MS in a clinical sample. Peak C, which was a minor product (less than 5% of the free platinum), coeluted with JM559 [bis-acetatoammine-chloro(cyclohexylalamine)hydroxoplatin um(IV)]. The cytotoxicity profile of all three metabolites in a panel of cisplatin-sensitive and -resistant human ovarian carcinoma cell lines was very close to that of the parent drug. In addition, the concentrations of JM118 reached in patients' plasma ultrafiltrate were comparable with the cytotoxic levels of the compound determined in the ovarian carcinoma panel of cell lines. Two metabolites were seen in patients but not in the in vitro incubation medium, suggesting the involvement of a possible enzymatic reaction. Thus, the biotransformation profile following oral administration of JM216 shows a variety of Pt(IV) and Pt(Il) metabolites in plasma that differ significantly from other systemically applied platinum drugs.


Assuntos
Antineoplásicos/metabolismo , Compostos Organoplatínicos/metabolismo , Administração Oral , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Estrutura Molecular , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/química , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas , Platina/sangue , Células Tumorais Cultivadas
16.
J Pharm Biomed Anal ; 13(12): 1493-8, 1995 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-8788134

RESUMO

The present study describes the application of on-line liquid chromatography-electrospray ionisation in conjunction with a high resolution magnetic sector mass spectrometer to identify metabolites of a platinum(IV) anticancer drug JM216 [bis(acetato)amminedichloro(cyclohexylamine)platinum(IV)] in human plasma. Four metabolites were identified following incubation of JM216 in human plasma: JM118 [amminedichlorocyclohexylamineplatinum(II)], a platinum(II) complex; JM383 [bis(acetato)amminedihydroxo(cyclohexylamine)platinum(IV)]; JM518 [bis(acetato)amminechloro(cyclohexylamine)hydroxoplatinum (IV)] and its isomer JM559. The platinum complexes mass spectra were dominated by the natriated [M + Na]+ ion. Elemental compositions of these natriated ions were confirmed by accurate mass measurement on a magnetic sector mass spectrometer in the course of LC/MS analysis. This study demonstrates the capability of direct LC-ESI/MS with accurate mass measurement for analysis of platinum complexes in biological samples. Our results suggest that LC-ESI/MS is a powerful technique for structure elucidation of novel metabolites, and could make valuable contributions to drug metabolism research.


Assuntos
Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Compostos Organoplatínicos/sangue , Compostos Organoplatínicos/farmacocinética , Biotransformação , Cromatografia Líquida , Ionização de Chama , Humanos , Isomerismo , Espectrometria de Massas , Platina/sangue , Polietilenoglicóis/análise , Ultrafiltração
17.
J Chromatogr A ; 712(1): 61-6, 1995 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-8556156

RESUMO

Bis(acetato)amminedichloro(cyclohexylamine) platinum(IV) (JM216) is a new orally administered platinum complex with antitumor properties, and is currently undergoing phase II clinical trials. When JM216 was incubated with human plasma ultrafiltrate, 93% of the platinum species were protein-bound and 7% were unbound. The unbound platinum complexes in the ultrafiltrates of human plasma were analysed using a liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS) method. Apart from the parent drug, four metabolites were identified and characterised. These include JM118 [amminedichloro(cyclohexylamine) platinum(II)], JM383 [bis(acetato)ammine(cyclohexylamine)dihydroxo platinum(IV)] and the two isomers JM559 and JM518 [bis(acetato)amminechloro(cyclohexylamine) hydroxo platinum(IV)]. Their elemental compositions were determined by accurate mass measurement during the LC analysis, to confirm their identities. Quantitation of these metabolites by off-line LC atomic absorption spectroscopy demonstrated that JM118 is the major metabolite in plasma from patients receiving JM216 treatment.


Assuntos
Antineoplásicos/sangue , Cromatografia Líquida de Alta Pressão , Espectrometria de Massas , Compostos Organoplatínicos/sangue , Antineoplásicos/uso terapêutico , Cromatografia Líquida de Alta Pressão/métodos , Feminino , Humanos , Íons , Espectrometria de Massas/métodos , Compostos Organoplatínicos/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Células Tumorais Cultivadas , Ultrafiltração
18.
Cancer Chemother Pharmacol ; 35(2): 169-73, 1994.
Artigo em Inglês | MEDLINE | ID: mdl-7987996

RESUMO

The compound 1069C85, methyl N-[6-(3,4,5-trimethoxybenzyloxy)imidazo(1,2b)-pyridazin-2-yl ] carbamate, is a novel synthetic tubulin binder currently undergoing phase I clinical trial. It was developed with a view to overcoming multidrug resistance and is given orally. Cytotoxicity studies in vitro against human ovarian carcinoma cell lines showed a lack of cross-resistance with cisplatin and no cross-resistance in two doxorubicin-resistant cell lines that exhibit high levels of resistance to both paclitaxel and vinblastine. Pharmacokinetic studies in BALB/c mice showed the oral bioavailability to be 20%, with 35% of the drug being excreted unchanged in the faeces over the first 24 h. Maximal plasma concentrations (Cmax) were achieved within 2 h of oral administration as compared with 7.5 min following i.v. injection. At a dose of 20 mg/kg, the tumour drug concentration exceeded the plasma Cmax by a factor of 1.5 and was within the in vitro cytotoxic concentration range. The drug showed a linear relationship between the dose and the area under the plasma concentration versus time curve (AUC) for doses of up to 20 mg/kg, above which no further increase in AUC was observed, possibly due to saturable absorption. 1069C85 is highly protein-bound (85%-99%) and appears to be subject to metabolism. The demonstration of cytotoxic activity against multidrug-resistant human tumour cell lines and the detection of potentially cytotoxic levels in an experimental tumour following oral administration support the choice of 1069C85 for clinical development.


Assuntos
Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Carbamatos/farmacocinética , Carbamatos/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Tubulina (Proteína)/metabolismo , Administração Oral , Animais , Antineoplásicos/sangue , Disponibilidade Biológica , Carbamatos/sangue , Cromatografia Líquida de Alta Pressão , Doxorrubicina/uso terapêutico , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/uso terapêutico , Piridazinas/sangue , Distribuição Tecidual , Células Tumorais Cultivadas/efeitos dos fármacos , Vimblastina/uso terapêutico
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