RESUMO
BACKGROUND: Glufosfamide (ß-D-glucosylisophosphoramide mustard, GLU) is an alkylating cytotoxic agent in which ifosforamide mustard (IPM) is glycosidically linked to the ß-D-glucose molecule. GLU exerted its cytotoxic effect as a targeted chemotherapy. Although, its cytotoxic efficacy in a number of cell lines, there were no experimental or clinical data available on the oncolytic effect of oxazaphosphorine drugs in hepatocellular carcinoma. Therefore, the main objective of the current study is to assess the cytotoxic potential of GLU for the first time in the hepatocellular carcinoma HepG2 cell line model. METHODS: Cytotoxicity was assayed by the MTT method, and half-maximal inhibitory concentration (IC50) was calculated. Flow cytometric analysis of apoptosis frequencies was measured by using Annexin V/PI double stain, an immunocytochemical assay of caspase-9, visualization of caspase-3, and Bcl2 gene expression were undertaken as apoptotic markers. Mitochondrial membrane potential was measured using the potentiometric dye; JC-1, as a clue for early apoptosis as well as ATP production, was measured by the luciferase-chemiluminescence assay. RESULTS: Glufosfamide induced cytotoxicity in HepG2 cells in a concentration- and time-dependent manner. The IC50 values for glufosfamide were significantly lower compared to ifosfamide. The frequency of apoptosis was much higher for glufosfamide than that of ifosfamide. The contents of caspase-9 and caspase-3 were elevated following exposure to GLU more than IFO. The anti-apoptotic Bcl2 gene expression, the mitochondrial membrane potential, and the cellular ATP levels were significantly decreased than in case of ifosfamide. CONCLUSIONS: The current study reported for the first time cytotoxicity activity of glufosfamide in HepG2 cells in vitro. The obtained results confirmed the higher oncolytic activity of glufosfamide than its aglycone ifosfamide. The generated data warrants further elucidations by in vivo study.
Assuntos
Ifosfamida , Neoplasias Hepáticas , Glucose/análogos & derivados , Células Hep G2 , Humanos , Ifosfamida/análogos & derivados , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genéticaRESUMO
The present work investigates the influence of different DNA damages caused by different isophosphoramide mustards on the 3-hydroxypropanal-assisted apoptotic antitumor activity of oxazaphosphorine cytostatics using I-aldophosphamide-perhydrothiazine (IAP) and mesyl-I-aldophosphamide-perhydrothiazine (SUM-IAP) for in-vitro and in-vivo experiments. IAP and SUM-IAP hydrolyze spontaneously to the corresponding I-aldophosphamide derivatives. They differ in the chemical structure of the alkylating moiety, whereas IAP has two chlorethyl groups in the SUM-IAP molecule, one chlorethyl group is substituted by a mesylethyl group. With both substances, cytotoxicity studies on P388 tumor cells in vitro and therapy experiments in mice bearing advanced growing P388 tumors were carried out. IAP was significantly more cytotoxic in-vitro than SUM-IAP, but the antitumor activity of SUM-IAP was by order of magnitude higher than the antitumor activity of IAP. The reason for these findings is discussed with respect to the enzymatic cleavage of the various I-aldophosphamide derivatives to the corresponding isophosphoramide mustards and 3-hydroxypropanal. Overall, the findings indicate that antitumor activity of ifosfamide and derivatives of ifosfamide can be improved considerably by altering the alkylating moiety of the molecule, but retaining the aldophosphamide structure.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Ifosfamida/farmacologia , Leucemia Experimental/tratamento farmacológico , Animais , Dano ao DNA , Feminino , Ifosfamida/análogos & derivados , CamundongosRESUMO
BACKGROUND/AIM: The oxazaphosphorines, ifosfamide and cyclophosphamide, represent a class of alkylating agents. The aim of the present in vitro study was to compare antileukemic activity of 4-hydroperoxyifosfamide (4-OOH-IF) and 4-hydroperoxycyclophosphamide (4-OOH-CP). MATERIALS AND METHODS: The experiments were performed on MOLT-4 and ML-1 cells. The research was conducted using flow cytometry fluorescein diacetate/propidium iodide (PI), fluorescein-conjugated annexin V/PI, CaspGLOW Red Active Caspase-8 and -9, CellEvent™ Caspase-3/7 Green assays, and tetramethylrhodamine ethyl ester test. RESULTS: 4-OOH-IF and 4-OOH-CP distinctly reduced cell viability and triggered apoptosis and necrosis, causing changes in intracellular esterase activity, plasma membrane structure and integrity, caspase activation, and mitochondrial membrane potential. The oxazaphosphorines were responsible for the different antileukemic activities. 4-Hydroperoxyifosfamide appeared to be less cytotoxic against the leukemia cells than 4-hydroperoxycyclophosphamide. MOLT-4 cells were more sensitive to the action of the oxazaphosphorines than ML-1 cells. CONCLUSION: The findings provide a new insight on the mechanisms of cytotoxic action of 4-OOH-IF and 4-OOH-CP on the human acute lymphoblastic and myeloblastic leukemia cells.
Assuntos
Antineoplásicos/farmacologia , Ciclofosfamida/análogos & derivados , Ifosfamida/análogos & derivados , Leucemia/metabolismo , Apoptose , Caspases/metabolismo , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ciclofosfamida/farmacologia , Esterases/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ifosfamida/farmacologia , Leucemia/tratamento farmacológico , Potencial da Membrana Mitocondrial/efeitos dos fármacosRESUMO
Oxazaphosphorines including cyclophosphamide, trofosfamide and ifosfamide (IFO) belong to the alkylating agent class and are indicated in the treatment of numerous cancers. However, IFO is subject to limiting side-effects in high-dose protocols. To circumvent IFO drawbacks in clinical practices, preactivated IFO analogs were designed to by-pass the toxic metabolic pathway. Among these IFO analogs, some of them showed the ability to self-assemble due to the use of a poly-isoprenyloxy chain as preactivating moiety. We present here, the in vitro activity of the nanoassembly formulations of preactivated IFO derivatives with a C-4 geranyloxy, farnesyloxy and squalenoxy substituent on a large panel of tumor cell lines. The chemical and colloidal stabilities of the geranyloxy-IFO (G-IFO), farnesyloxy-IFO (F-IFO) and squalenoxy-IFO (SQ-IFO) NAs were further evaluated in comparison to their free formulation. Finally, pharmacokinetic parameters and maximal tolerated dose of the most potent preactivated IFO analog (G-IFO) were determined and compared to IFO, paving the way to in vivo studies.
Assuntos
Antineoplásicos Alquilantes/administração & dosagem , Ifosfamida/análogos & derivados , Ifosfamida/administração & dosagem , Nanoestruturas/administração & dosagem , Animais , Antineoplásicos Alquilantes/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Humanos , Ifosfamida/química , Ifosfamida/farmacocinética , Masculino , Dose Máxima Tolerável , Camundongos Nus , Nanoestruturas/química , PrenilaçãoRESUMO
The antitumor drug, ifosfamide (IFO), requires activation by cytochrome P450 (CYP) to form the active metabolite, 4-hydroxyisfosfamide (4-OHIFO), leading to toxic by-products at high dose. In order to overcome these drawbacks, preactivated ifosfamide derivatives (RXIFO) were designed to release 4-OHIFO without CYP involvement. A high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed for the simultaneous quantification of 4-OHIFO, IFO and four derivatives RXIFO in mouse plasma using multiple reaction monitoring. Because of its instability in plasma, 4-OHIFO was immediately converted to the semi-carbazone derivative, 4-OHIFO-SCZ. For the six analytes, the calibration curves were linear from 20 to 5000ng/mL in 50µL plasma and the lower limit of quantitation was determined at 20ng/mL with accuracies within ±10% of nominal and precisions less than 12%. Their recoveries ranged from 62 to 96% by using liquid-liquid extraction. With an improved assay sensitivity compared to analogues, the derivative 4-OHIFO-SCZ was stable in plasma at 4°C for 24h and at -20°C for three months. For all compounds, the assay was validated with accuracies within ±13% and precisions less than 15%. This method was applied to a comparative pharmacokinetic study of 4-OHIFO from IFO and three derivatives RXIFO in mice. This active metabolite was produced by some of the novel conjugates with good pharmacokinetic properties.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ifosfamida/análogos & derivados , Ifosfamida/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Feminino , Ifosfamida/química , Ifosfamida/farmacocinética , Modelos Lineares , Camundongos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
Oxazaphosphorines are alkylating agents used in routine clinical practices for treatment of cancer for many years. They are antitumor prodrugs that require cytochrome P450 bioactivation leading to 4-hydroxy derivatives. In the case of ifosfamide (IFO), the bioactivation produces two toxic metabolites: acrolein, a urotoxic compound, concomitantly generated with the isophosphoramide mustard; and chloroacetaldehyde, a neurotoxic and nephrotoxic compound, arising from the oxidation of the side chains. To improve the therapeutic index of IFO, we have designed preactivated IFO derivatives with the covalent binding of several O- and S-alkyl moieties including polyisoprenoid groups at the C-4 position of the oxazaphosphorine ring to avoid cytochrome bioactivation favoring the release of the active entity and limiting the chloroacetaldehyde release. Thanks to the grafted terpene moieties, some of these new conjugates demonstrated spontaneous self-assembling properties into nanoassemblies when dispersed in water. The cytotoxic activities on a panel of human tumor cell lines of these novel oxazaphosphorines, in bulk form or as nanoassemblies, and the release of 4-hydroxy-IFO from these preactivated IFO analogues in plasma are reported.
Assuntos
Antineoplásicos Alquilantes/síntese química , Ifosfamida/análogos & derivados , Mostardas de Fosforamida/metabolismo , Pró-Fármacos/síntese química , Antineoplásicos Alquilantes/metabolismo , Antineoplásicos Alquilantes/farmacologia , Linhagem Celular Tumoral , Desenho de Fármacos , Humanos , Ifosfamida/metabolismo , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologiaRESUMO
This study investigated the effects of umbelliferone (UF) on alcoholic fatty liver and its underlying mechanism. Rats were fed a Lieber-DeCarli liquid diet with 36% of calories as alcohol with or without UF (0.05 g/L) for 8 weeks. Pair-fed rats received an isocaloric carbohydrate liquid diet. UF significantly reduced the severity of alcohol-induced body weight loss, hepatic lipid accumulation and droplet formation, and dyslipidemia. UF decreased plasma AST, ALT, and γGTP activity. UF significantly reduced hepatic cytochrome P450 2E1 activities and increased alcohol dehydrogenase and aldehyde dehydrogenase 2 activities compared to the alcohol control group, which resulted in a lower plasma acetaldehyde level in the rats that received UF. Chronic alcohol exposure inhibited hepatic AMPK activation compared to the pair-fed rats, which was reversed by UF supplementation. UF also significantly suppressed the lipogenic gene expression (SREBP-1c, SREBP-2, FAS, CIDEA, and PPARγ) and elevated the fatty acid oxidation gene expression (PPARα, Acsl1, CPT, Acox, and Acaa1a) compared to the alcohol control group, which could lead to inhibition of FAS activity and stimulation of CPT and fatty acid ß-oxidation activities in the liver of chronic alcohol-fed rats. These results indicated that UF attenuated alcoholic steatosis through down-regulation of SREBP-1c-mediated lipogenesis and up-regulation of PPARα-mediated fatty acid oxidation. Therefore, UF may provide a promising natural therapeutic strategy against alcoholic fatty liver.
Assuntos
Fígado Gorduroso Alcoólico/tratamento farmacológico , PPAR alfa/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Umbeliferonas/uso terapêutico , Álcool Desidrogenase/metabolismo , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , Animais , Citocromo P-450 CYP2E1/metabolismo , Suplementos Nutricionais , Hipolipemiantes/uso terapêutico , Ifosfamida/análogos & derivados , Ifosfamida/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Proteínas Mitocondriais/metabolismo , PPAR alfa/fisiologia , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologiaRESUMO
BACKGROUND: This phase I trial assessed safety, pharmacokinetics (PK), dose limiting toxicity (DLT), maximum tolerated dose and recommended dose (RD) of the combination of sorafenib plus ifosfamide in patients with advanced sarcoma. METHODS: Twelve sarcoma patients (9 soft-tissue, 3 bone sarcoma) were treated with sorafenib plus ifosfamide (starting doses 200 mg bid and 6 g/m(2) respectively). A 3 + 3 dose escalation design with cohorts of 3-6 patients was used. A study to assess the in vitro efficacy of the combination was also conducted. RESULTS: Three DLTs were observed: fatigue grade 4 with sorafenib 400 mg bid plus ifosfamide 6 g/m(2) and encephalopathy and emesis grade 3 with sorafenib 400 mg bid plus ifosfamide 7.5 g/m(2). Other toxicities included diarrhea, hand-foot syndrome, mucositis, neutropenia, skin rash and thrombocytopenia. There were no relevant effects on PK of sorafenib but an increase in ifosfamide active metabolite 4-hydroxy-ifosfamide was observed. Eight patients achieved stable disease lasting more than 12 weeks. An additive effect was observed in vitro. CONCLUSIONS: RD was sorafenib 400 mg bid plus ifosfamide 6 g/m(2), allowing administration of active doses of both agents. Limited preliminary antitumor activity was also observed. A phase II study is currently ongoing.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sarcoma/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Ifosfamida/análogos & derivados , Ifosfamida/farmacologia , Masculino , Pessoa de Meia-Idade , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/farmacologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacologia , Sarcoma/metabolismo , Sorafenibe , Adulto Jovem , Quinases raf/antagonistas & inibidoresRESUMO
The prodrugs cyclophosphamide (CP) and ifosfamide (IF) each metabolize to an active alkylating agent through a cytochrome P450-mediated oxidation at the C-4 position. Competing with this activation pathway are enzymatic oxidations at the exocyclic α and α' carbons, which result in dechloroethylation of CP and IF. The incidence of oxidation at one position relative to another is believed to be at least one factor underlying the high degree of interpatient variability in both CP and IF pharmacokinetics. As standards for the mass spectrometry quantification of dechloroethylation, the following were synthesized: (1) [4,4,5,5-(2) H4 ]-2-dechloroethylcyclophosphamide (equivalent to [4,4,5,5-(2) H4 ]-3-dechloroethylifosfamide); (2) [α,α,4,4,5,5-(2) H6 ]-2-dechloroethylcyclophosphamide (equivalent to [α,α,4,4,5,5-(2) H6 ]-3-dechloroethylifosfamide); and (3) [α,α,4,4,5,5-(2) H6 ]-2-dechloroethylifosfamide. The common precursor to all of the target compounds was [2,2,3,3-(2) H4 ]-3-aminopropanol. A one-pot reaction of this compound with POCl3 and unlabeled or labeled 2-chloroethylamine hydrochloride gave the d4 and d6 labeled 2-dechloroethylcyclophosphamides. The construction of the 2-dechloroethylifosfamide from the aminopropanol required five discreet steps. Optimization of the synthetic pathways and stability studies are discussed.
Assuntos
Ciclofosfamida/análogos & derivados , Deutério/química , Ifosfamida/análogos & derivados , Marcação por Isótopo , Ciclofosfamida/síntese química , Ifosfamida/síntese química , Espectrometria de Massas/métodosRESUMO
Oxazaphosphorines belong to a group of alkylating agents. Mafosfamide cyclohexylamine salt (D-17272), 4-hydro-peroxy-cyclophosphamide (D-18864) and glufosfamide (D-19575, beta-D-glucose-isophosphoramide mustard) are new generation oxazaphosphorines. The objective of the present study was to compare the cytotoxic action of these oxazaphosphorine compounds against human histiocytic lymphoma U937 cells. The chemical structures of the oxazaphosphorines were responsible for the different responses of U937 cells. The cytotoxic effects of D-17272, D-18864, and D-19575 on U937 cells depended on the agent tested, its dose, and the time intervals after the oxazaphosphorine application. Among the oxazaphosphorine agents, D-18864 appeared to be the most cytotoxic, and D-19575 was characterized by the lowest cytotoxicity. The in vitro cytotoxic activities of the oxazaphosphorines were strongly associated with their cell death inducing potential.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Ciclofosfamida/análogos & derivados , Glucose/análogos & derivados , Ifosfamida/análogos & derivados , Linfoma Difuso de Grandes Células B/patologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mostardas de Fosforamida/farmacologia , Proliferação de Células/efeitos dos fármacos , Ciclofosfamida/farmacologia , Citometria de Fluxo , Glucose/farmacologia , Humanos , Ifosfamida/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Necrose , Células Tumorais CultivadasRESUMO
Because of the changed metabolic behaviors of cancer cells, tumor cells uptake a corresponding larger amount of glucose in physiological condition when compared with normal cells. And they were prone to metabolize glucose for generating energy in anaerobic glycolysis ways in order to grow quickly. Anaerobic glycolysis consumes more glucose than aerobic way when the same amount of energy is obtained, which also results in large demand of glucose in tumor cells. This review briefly describes therapy methods related to characteristic mentioned above, and summarizes the research progress of drugs, diagnostic reagents and carriers conjugated with glucose, glucose derivatives or other kinds of sugars for cancer targeting. Furthermore, typically relative research reports from 2012 till now were listed and analyzed.
Assuntos
Glucose/metabolismo , Glicoconjugados , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/uso terapêutico , Portadores de Fármacos , Metabolismo Energético , Glucose/análogos & derivados , Glucose/química , Glucose/uso terapêutico , Glicoconjugados/química , Glicoconjugados/uso terapêutico , Glicólise , Glicosídeos/química , Humanos , Ifosfamida/análogos & derivados , Ifosfamida/química , Ifosfamida/uso terapêutico , Neoplasias/metabolismo , Nitroimidazóis/química , Radiossensibilizantes/químicaRESUMO
INTRODUCTION: Drug development is a complex and risky enterprise. Clinical development must be a thoroughly paced process sequenced by clinical and developmental questions logically ordered. Drug development parameters are changing due to better insights in system biology and mechanisms of actions. Therefore, there is a need to revisit how clinical trials are designed and sequenced. AREAS COVERED: In the context of this paper, the development of glufosfamide is placed in perspective of possible new trends for more optimal drug development. Glufosfamide is an alkylating agent with a favorable safety profile as its metabolic activation does not lead to the release of toxic metabolites such as acrolein. In addition, its cellular uptake mediated through the transmembrane receptors of glucose makes it an attractive agent for the treatment of highly proliferative tumors cells. These observations have served the rationale to bring this agent to the clinic from Phase I up to Phase III with a focus on pancreatic cancer. The pathways for its development have been challenging due in part to the fact that there is no proof of mechanism-based study for any alkylating agent, even those used in the clinic. EXPERT OPINION: Solid mechanism and translational research-based clinical trials providing evidence on the mechanism of action and how the agent interacts with the biology of the targeted disease are today an absolute requirement for the development of new agents. Optimal clinical trial design must complement system biology understanding so that 'trials designed to learn' may give robust grounds to 'clinical trials designed to conclude'.
Assuntos
Alquilantes/uso terapêutico , Antineoplásicos/uso terapêutico , Glucose/análogos & derivados , Ifosfamida/análogos & derivados , Neoplasias/tratamento farmacológico , Alquilantes/farmacologia , Animais , Antineoplásicos/farmacologia , Descoberta de Drogas , Glucose/farmacologia , Glucose/uso terapêutico , Humanos , Ifosfamida/farmacologia , Ifosfamida/uso terapêutico , Neoplasias/metabolismoRESUMO
Palifosfamide, the DNA-alkylating metabolite of ifosfamide (IFOS), has been synthesized as a stabilized tris or lysine salt and found to have preclinical and clinical antitumor activity. Stabilized palifosfamide overcomes limitations of IFOS because of patient-to-patient variability in response resulting from variable prodrug activation, resistance and toxicities of metabolic byproducts, acrolein and chloroacetaldehyde. Palifosfamide represents an effective alternative to IFOS and other DNA-alkylating prodrugs. The antitumor activities of stabilized palifosfamide were investigated in vivo. Dose response, route and schedule of administration, and interaction with docetaxel or doxorubicin were investigated in NCr-nu/nu mice bearing established orthotopic mammary MX-1 tumor xenografts. Oral activity was investigated in P388-1 leukemia in CD2F1 mice. Oral and intraperitoneal bioavailabilities were compared in Sprague-Dawley rats. Stabilized palifosfamide administered by optimized regimens suppressed MX-1 tumor growth (P<0.05) by greater than 80% with 17% complete antitumor responses and up to three-fold increase in time to three tumor doublings over controls. Median survival in the P388-1 (P<0.001) model was increased by 9 days over controls. Oral bioavailability in rats was 48-73% of parenteral administration, and antitumor activity in mice was equivalent by both routes. Treatment with palifosfamide-tris combined with docetaxel or doxorubicin at optimal regimens resulted in complete tumor regression in 62-75% of mice. These studies support investigation of stabilized palifosfamide in human cancers by parenteral or oral administration as a single agent and in combination with other approved drugs. The potential for clinical translation of the cooperative interaction of palifosfamide-tris with doxorubicin by intravenous administration is supported by results from a recent randomized Phase-II study in unresectable or metastatic soft-tissue sarcoma.
Assuntos
Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Ifosfamida/análogos & derivados , Leucemia Experimental/tratamento farmacológico , Lisina/análogos & derivados , Neoplasias Mamárias Experimentais/tratamento farmacológico , Mostardas de Fosforamida/uso terapêutico , Taxoides/uso terapêutico , Administração Oral , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Disponibilidade Biológica , Intervalo Livre de Doença , Docetaxel , Relação Dose-Resposta a Droga , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Ifosfamida/administração & dosagem , Ifosfamida/farmacocinética , Ifosfamida/uso terapêutico , Injeções Intravenosas , Lisina/administração & dosagem , Lisina/farmacocinética , Lisina/uso terapêutico , Masculino , Camundongos , Camundongos Nus , Mostardas de Fosforamida/administração & dosagem , Mostardas de Fosforamida/farmacocinética , Ratos , Ratos Sprague-Dawley , Taxoides/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Soft tissue sarcomas are rare tumours in adults and therefore require a multidisciplinary approach for optimal management. In the metastatic setting, chemotherapy is the primary modality of therapy. Doxorubicin alone or in combination with ifosfamide or dacarbazine has been the backbone of therapy since the 1970s. There is considerable activity for gemcitabine and docetaxel in leiomyosarcoma and for paclitaxel in angiosarcoma. Newer agents such as trabectedin and eribulin may have a role in certain sarcoma subtypes. Palifosfamide may offer a safer alternative to ifosfamide in the future. Many sarcomas have molecular aberrations that can be targeted. Agents that inhibit the insulin-like growth factor receptor-1, mammalian target of rapamycin and vascular endothelial growth factor are currently being investigated.
Assuntos
Antineoplásicos/administração & dosagem , Sarcoma/tratamento farmacológico , Neoplasias de Tecidos Moles/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Dioxóis/administração & dosagem , Doxorrubicina/administração & dosagem , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/análogos & derivados , Lisina/administração & dosagem , Lisina/análogos & derivados , Paclitaxel/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Tetra-Hidroisoquinolinas/administração & dosagem , Trabectedina , GencitabinaRESUMO
Among antitumor oxazaphosphorine drugs, the prodrug ifosfamide (IFO) and its analogs require metabolic activation by specific liver cytochrome P450 (CYP) enzymes to become therapeutically active. New 7,9-dimethyl-ifosfamide analogs have shown greater cytotoxic activity than IFO, whereas side-chain oxidation still occurred leading to monochloroacetone after N-dechloropropylation. A sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was developed and validated for the simultaneous quantitation of the prodrug 7S,9S-dimethyl-ifosfamide (diMeIFO) and its two inactive metabolites, N(2)- and N(3)-deschloropropyl-dimethylifosfamide (N(2)-DCP-diMeIFO and N(3)-DCP-diMeIFO) in mouse plasma. After protein precipitation with methanol, the analytes were separated by isocratic reversed-phase chromatography with (methanol/ammonium formate pH 5.5, 60:40, v/v) and detected by tandem mass spectrometry using multiple reaction monitoring of transitions ions m/z 289â168 for diMeIFO, m/z 213â168 for N(2)-DCP-diMeIFO, m/z 213â92 for N(3)-DCP-diMeIFO and m/z 261â154 for IFO (internal standard). The calibration curves were linear over the concentration range of 20-10,000ng/mL for the three analytes. Mean extraction recoveries from mouse plasma were 99, 96, 99 and 100% for diMeIFO, N(2)-DCP-diMeIFO, N(3)-DCP-diMeIFO and IFO, respectively. The lower limit of quantitation for diMeIFO and its metabolites was 20 ng/mL in 50 µL plasma. The method was accurate with calculated bias from -5.8 to 4.0% for diMeIFO, from -1.1 to 10.6% for N(2)-DCP-diMeIFO and from -6.9 to 9.8% for N(3)-DCP-diMeIFO, and precise with coefficients of variation lower than 6.8%, 7.8% and 14.3%, respectively. The assay was successfully applied to a preliminary pharmacokinetic study of diMeIFO and of its metabolites in mice.
Assuntos
Cromatografia Líquida/métodos , Ifosfamida/análogos & derivados , Ifosfamida/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Estabilidade de Medicamentos , Feminino , Humanos , Ifosfamida/farmacocinética , Análise dos Mínimos Quadrados , Camundongos , Camundongos Nus , Reprodutibilidade dos Testes , Rabdomiossarcoma/sangue , Rabdomiossarcoma/metabolismo , Sensibilidade e EspecificidadeRESUMO
Glufosfamide (ß-D-glucose-isophosphoramide mustard, D-19575) belongs to the oxazaphosphorine class. Glufosfamide is a novel glucose conjugate of ifosfamide in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is glycosidically linked to the ß-D-glucose molecule. Glufosfamide represents an attractive new agent for cancer therapy. Its mode of action on normal and pathological cells is still under experimental and clinical investigations. An assessment of the anticancer potential of glufosfamide is of key importance in therapy. The researchers reviewed the current knowledge available on glufosfamide tested in the preclinical studies/clinical trials, based on a collection of the original papers and conference abstracts published and relevant articles searched in the SCOPUS and MEDLINE database and websites.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Glucose/análogos & derivados , Ifosfamida/análogos & derivados , Neoplasias/tratamento farmacológico , Mostardas de Fosforamida/farmacologia , Antineoplásicos Alquilantes/farmacocinética , Antineoplásicos Alquilantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Desenho de Fármacos , Glucose/efeitos adversos , Glucose/farmacocinética , Glucose/farmacologia , Glucose/uso terapêutico , Humanos , Ifosfamida/efeitos adversos , Ifosfamida/farmacocinética , Ifosfamida/farmacologia , Ifosfamida/uso terapêutico , Neoplasias/patologia , Mostardas de Fosforamida/efeitos adversos , Mostardas de Fosforamida/farmacocinética , Mostardas de Fosforamida/uso terapêuticoRESUMO
PURPOSE: The aim of this study was to examine the penetration of ifosfamide (IFO) and 4-hydroxy-ifosfamide (4-OH-IFO) into the CSF of human adults and to evaluate the influence of blood-CSF barrier (BCB) function. METHODS: In 12 adult patients with a malignant CNS disease treated with IFO 1,300-2,000 mg/m(2)/d as a 3-hour intravenous infusion, 17 CSF samples were collected within 10 min after the end of IFO infusion. In 8 of these patients, the CSF was obtained in up to 5 sequential 2-ml portions to detect a potential caudocranial concentration gradient. Additionally, blood was collected before treatment and immediately following IFO infusion. RESULTS: IFO was detected in all 17 CSF samples at a median concentration of 79.24 µmol/l (39.27-176.73) and a median CSF/plasma ratio of 0.38 (0.18-0.72). 4-OH-IFO was detected in 11 CSF samples from 7 patients at a median concentration of 4.1 µmol/l (2.44-36.03) and a median CSF/plasma ratio of 3.07 (0.62-29.12). 4-OH-IFO was undetectable in 6 CSF samples from 5 patients and in one plasma sample. Both CSF drug concentrations and their CSF/plasma quotients neither correlated with steroid comedication nor with albumin quotients (QAlb). CONCLUSIONS: Both IFO and 4-OH-IFO can penetrate into the CSF of human adults without a correlation to CSF turnover. In contrast to IFO, 4-OH-IFO CSF penetration is not reliable with levels ranging between undetectable and exceeding those in the corresponding plasma.
Assuntos
Antineoplásicos Alquilantes/líquido cefalorraquidiano , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Ifosfamida/análogos & derivados , Ifosfamida/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Alquilantes/farmacocinética , Barreira Hematoencefálica/metabolismo , Feminino , Humanos , Ifosfamida/farmacocinética , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , PermeabilidadeRESUMO
Oxazaphosphorines are a class of DNA alkylating agents. The aim of the present study was to compare the possible influence of three new generation oxazaphosphorines, D-17272 (mafosfamide cyclohexylamine salt), D-18864 (4-hydro-peroxy-cyclophosphamide), and D-19575 (glufosfamide, beta-D-glucose-isophosphoramide mustard) on DNA damage induction in the human histiocytic lymphoma U937 cells. The flow cytometry APO-BRDU assay, based on the TUNEL method, was used for the in situ detection of DNA strand breaks. After exposure of U937 cells to the oxazaphosphorines, the patterns of temporary changes in the frequency of TUNEL positive U937 cells, expressing DNA breakage, were determined. The effects of the oxazaphosphorines on U937 cells were dependent on the agent tested and its dose, and the time intervals after the drug application. The different potential of D-17272, D-18864 and D-19575 to induce DNA strand breakage in the human histiocytic lymphoma U937 cells was shown.
Assuntos
Antineoplásicos Alquilantes/farmacologia , Ciclofosfamida/análogos & derivados , Quebras de DNA/efeitos dos fármacos , Glucose/análogos & derivados , Ifosfamida/análogos & derivados , Mostardas de Fosforamida/farmacologia , Ciclofosfamida/farmacologia , Glucose/farmacologia , Humanos , Ifosfamida/farmacologia , Células U937RESUMO
Ifosfamide is a chemotherapeutic prodrug used in the treatment of several tumor entities, including bone and soft-tissue sarcoma. However, the application of high-dose ifosfamide is not feasible because of severe side effects caused by metabolites. The active metabolite isophosphoramide mustard is not suitable for administration because of chemical instability. ZIOPHARM Oncology Inc, under license from Dekk-Tec Inc, is developing palifosfamide, a formulation of isophosphoramide mustard with tris(hydroxymethyl)aminomethane salt-stabilization (palifosfamide-tris) and previously with lysine-stabilization (palifosfamide-lys). Preclinical studies and phase I and I/II clinical trials demonstrated that palifosfamide-tris had an antitumor efficiency comparable or superior to that of ifosfamide. Patients treated with palifosfamide-tris did not display any of the neurotoxic or nephrotoxic side effects associated with ifosfamide. At the time of publication, data from phase II trials were being evaluated and phase III trials were being planned. palifosfamide-tris is expected to be a safer and less toxic alternative to ifosfamide; however, considering other new approaches under investigation for tumors such as sarcoma, such as molecular-based treatment strategies, it is unclear what position palifosfamide-tris might occupy on the market.
Assuntos
Ifosfamida/análogos & derivados , Lisina/análogos & derivados , Sarcoma/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/fisiopatologia , Ensaios Clínicos como Assunto , Avaliação Pré-Clínica de Medicamentos , Humanos , Ifosfamida/efeitos adversos , Ifosfamida/farmacologia , Ifosfamida/uso terapêutico , Lisina/efeitos adversos , Lisina/farmacologia , Lisina/uso terapêutico , Sarcoma/fisiopatologia , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/fisiopatologiaRESUMO
OBJECTIVES: A dose-escalation study of glufosfamide plus gemcitabine showed that the combination could be administered safely at full doses. The purpose of this phase II study was to evaluate the safety and efficacy of this combination in chemotherapy-naive pancreatic adenocarcinoma. METHODS: Eligible patients had metastatic and/or locally advanced pancreatic adenocarcinoma, Karnofsky performance status >or=70, creatinine clearance (CrCL) >or=60 mL/min, and acceptable organ function. Patients received glufosfamide 4500 mg/m intravenous on day 1 and gemcitabine 1000 mg/m intravenous on Days 1, 8, and 15 of every 28-day cycle. The primary end point was response rate. RESULTS: Twenty-nine patients were enrolled; 14 male, median age 58 years. Twenty-three (79%) patients had distant metastases. Median cycles on treatment was 4 (range: 1-18+). Of 28, 5 (18%; 95% CI: 6%-37%) patients had a confirmed partial response (median duration: 8.4 months) and 1 had an unconfirmed partial response. Eleven patients (39%) had stable disease. Median progression-free survival was 3.7 months, median overall survival was 6 months, and 1-year survival was 32%. Grade 3/4 neutropenia occurred in 23 (79%) patients and grade 3/4 thrombocytopenia in 10 (34%) patients. The CrCL fell below 60 mL/min in 10 of 27 (37%) patients. Renal failure occurred in 4 patients. Decrease in CrCL was correlated with glufosfamide and isophosphoramide mustard pharmacokinetic area under the curve. CONCLUSIONS: The combination of glufosfamide plus gemcitabine is active in pancreatic cancer; however, hematologic and renal toxicity were pronounced. Alternative dosing of glufosfamide plus gemcitabine should be explored.