RESUMO
PURPOSE OF REVIEW: As our molecular understanding of bladder cancer continues to advance, more and more novel agents are entering clinical trials across the spectrum of bladder cancer stages. The clinical trial activity for non-muscle invasive bladder cancer (NMIBC) has been boosted further by the evolution of specific disease states that set more uniform inclusion criteria for clinical trial design. Here, we aimed to review the current clinical trials landscape in non-muscle invasive bladder cancer with respect to these disease states. RECENT FINDINGS: Most active clinical trials focus on high-risk NMIBC in either the BCG-naïve or BCG-unresponsive setting. Strict criteria to define the disease state and a clear pathway to drug registration have encouraged trials for patients with BCG-unresponsive NMIBC. The most promising potential breakthroughs for BCG-naïve patients include alternative BCG strains, immune-priming with intradermal BCG vaccination, and systemic immune checkpoint blockade. The latter therapy is also being actively investigated in multiple trials in BCG-unresponsive NMIBC, along with novel viral agents such as INSTILADRIN (nadofaragene firadenovec) and targeted agents such as oportuzumab monatox. After many years of relative stagnation, multiple new therapies currently under investigation in well-designed clinical trials appear poised for routine clinical implementation in the near future. These therapies should dramatically improve the outcome of patients with NMIBC. We can look forward to the challenges of biomarker-driven drug selection, optimal drug sequencing, and rational combination therapies.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Vacina BCG/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Administração Intravesical , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Aziridinas/uso terapêutico , Carcinoma de Células de Transição/patologia , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Indolquinonas/uso terapêutico , Injeções Intradérmicas , Mitomicina/uso terapêutico , Músculo Liso/patologia , Invasividade Neoplásica , Polissacarídeos Bacterianos/uso terapêutico , Proteínas/uso terapêutico , Proteínas Recombinantes de Fusão , Tamoxifeno/uso terapêutico , Vacinas Tíficas-Paratíficas/uso terapêutico , Neoplasias da Bexiga Urinária/patologia , Procedimentos Cirúrgicos UrológicosRESUMO
This review examines the vast catalytic and therapeutic potential offered by type I (i.e. oxygen-insensitive) nitroreductase enzymes in partnership with nitroaromatic prodrugs, with particular focus on gene-directed enzyme prodrug therapy (GDEPT; a form of cancer gene therapy). Important first indications of this potential were demonstrated over 20 years ago, for the enzyme-prodrug pairing of Escherichia coli NfsB and CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide]. However, it has become apparent that both the enzyme and the prodrug in this prototypical pairing have limitations that have impeded their clinical progression. Recently, substantial advances have been made in the biodiscovery and engineering of superior nitroreductase variants, in particular development of elegant high-throughput screening capabilities to enable optimization of desirable activities via directed evolution. These advances in enzymology have been paralleled by advances in medicinal chemistry, leading to the development of second- and third-generation nitroaromatic prodrugs that offer substantial advantages over CB1954 for nitroreductase GDEPT, including greater dose-potency and enhanced ability of the activated metabolite(s) to exhibit a local bystander effect. In addition to forging substantial progress towards future clinical trials, this research is supporting other fields, most notably the development and improvement of targeted cellular ablation capabilities in small animal models, such as zebrafish, to enable cell-specific physiology or regeneration studies.
Assuntos
Aziridinas/uso terapêutico , Proteínas de Escherichia coli , Terapia Genética/métodos , Neoplasias Experimentais/terapia , Nitrorredutases , Pró-Fármacos/uso terapêutico , Animais , Evolução Molecular Direcionada , Proteínas de Escherichia coli/biossíntese , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/uso terapêutico , Humanos , Neoplasias Experimentais/genética , Neoplasias Experimentais/patologia , Nitrorredutases/biossíntese , Nitrorredutases/genética , Nitrorredutases/uso terapêuticoRESUMO
Tumor therapy escape due to undesired side effects induced by treatment, such as prosurvival autophagy or cellular senescence, is one of the key mechanisms of resistance that eventually leads to tumor dormancy and recurrence. Glioblastoma is the most frequent and practically incurable neoplasm of the central nervous system; thus, new treatment modalities have been investigated to find a solution more effective than the currently applied standards based on temozolomide. The present study examined the newly synthesized compounds of aziridine-hydrazide hydrazone derivatives to determine their antineoplastic potential against glioblastoma cells in vitro. Although the output of our investigation clearly demonstrates their proapoptotic activity, the cytotoxic effect appeared to be blocked by treatment-induced autophagy, the phenomenon also detected in the case of temozolomide action. The addition of an autophagy inhibitor, chloroquine, resulted in a significant increase in apoptosis triggered by the tested compounds, as well as temozolomide. The new aziridine-hydrazide hydrazone derivatives, which present cytotoxic potential against glioblastoma cells comparable to or even higher than that of temozolomide, show promising results and, thus, should be further investigated as antineoplastic agents. Moreover, our findings suggest that the combination of an apoptosis inducer with an autophagy inhibitor could optimize chemotherapeutic efficiency, and the addition of an autophagy inhibitor should be considered as an optional adjunctive therapy minimizing the risk of tumor escape from treatment.
Assuntos
Antineoplásicos , Aziridinas , Glioblastoma , Humanos , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Cloroquina/farmacologia , Hidrazonas/farmacologia , Hidrazinas/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Autofagia , Aziridinas/farmacologia , Aziridinas/uso terapêuticoRESUMO
Gene-directed enzyme prodrug therapy (GDEPT) is a promising and emerging strategy that attempts to limit the systemic toxicity inherent to cancer chemotherapy by means of tumor-targeted delivery and expression of an exogenous gene whose product converts nontoxic prodrug(s) into activated cytotoxic agent(s). The bacterial nitroreductase (NTR) enzyme, coupled with its substrate prodrug 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), is a promising GDEPT strategy that has reached clinical trials. However, no strategy exists to visually monitor and quantitatively evaluate the therapeutic efficacy of NTR/CB1954 prodrug therapy in cells and imaging in living animals. As the success of any GDEPT is dependent upon the efficiency of transgene expression in vivo, we developed a safe, sensitive and reproducible noninvasive imaging method to monitor NTR transgene expression that would allow quantitative assessment of both therapeutic efficacy and diagnostic outcome of NTR/CB1954 prodrug therapy in the future. Here, we investigate the use of a novel fluorescent imaging dye CytoCy5S (a Cy5-labeled quenched substrate of NTR enzyme) on various cancer cell lines in vitro and in NTR-transfected tumor-bearing animals in vivo. CytoCy5S-labeled cells become fluorescent at 'red-shifted' wavelengths (638 nm) when reduced by cellular NTR enzyme and remains trapped within the cells for extended periods of time. The conversion and entrapment was dynamically recorded using a time-lapsed microscopy. Systemic and intratumoral delivery of CytoCy5S to NTR-expressing tumors in animals indicated steady and reproducible signals even 16 h after delivery (P<0.001). This is the first study to address visual monitoring and quantitative evaluation of NTR activity in small animals using CytoCy5S, and establishes the capability of NTR to function as an imageable reporter gene.
Assuntos
Aziridinas/metabolismo , Imagem Molecular , Nitrorredutases/genética , Nitrorredutases/metabolismo , Pró-Fármacos/metabolismo , Animais , Aziridinas/uso terapêutico , Linhagem Celular , Ativação Enzimática/genética , Expressão Gênica , Ordem dos Genes , Vetores Genéticos , Humanos , Mucosa Intestinal/metabolismo , Intestinos/microbiologia , Cinética , Metagenoma/genética , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Neoplasias/genética , Pró-Fármacos/uso terapêutico , Transfecção , Transplante HeterólogoRESUMO
Advances in the field of cancer immunotherapy have stimulated renewed interest in adenoviruses as oncolytic agents. Clinical experience has shown that oncolytic adenoviruses are safe and well tolerated but possess modest single-agent activity. One approach to improve the potency of oncolytic viruses is to utilise their tumour selectivity to deliver genes encoding prodrug-activating enzymes. These enzymes can convert prodrugs into cytotoxic species within the tumour; however, these cytotoxins can interfere with viral replication and limit utility. In this work, we evaluated the activity of a nitroreductase (NTR)-armed oncolytic adenovirus ONYX-411NTR in combination with the clinically tested bioreductive prodrug PR-104. Both NTR-expressing cells in vitro and xenografts containing a minor population of NTR-expressing cells were highly sensitive to PR-104. Pharmacologically relevant prodrug exposures did not interfere with ONYX-411NTR replication in vitro. In vivo, prodrug administration increased virus titre and improved virus distribution within tumour xenografts. Colonisation of tumours with high ONYX-411NTR titre resulted in NTR expression and prodrug activation. The combination of ONYX-411NTR with PR-104 was efficacious against HCT116 xenografts, whilst neither prodrug nor virus were active as single agents. This work highlights the potential for future clinical development of NTR-armed oncolytic viruses in combination with bioreductive prodrugs.
Assuntos
Aziridinas , Neoplasias , Terapia Viral Oncolítica , Pró-Fármacos , Adenoviridae , Aziridinas/farmacologia , Aziridinas/uso terapêutico , Humanos , Neoplasias/terapia , Compostos de Mostarda Nitrogenada , Nitrorredutases/genética , Nitrorredutases/metabolismo , Vírus Oncolíticos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêuticoRESUMO
BACKGROUND: This trial describes a first-in-man evaluation of RH1, a novel bioreductive drug activated by DT-diaphorase (DTD), an enzyme overexpressed in many tumours. PATIENTS AND METHODS: A dose-escalation phase I trial of RH1 was carried out. The primary objective was to establish the maximum tolerated dose (MTD) of RH1. Secondary objectives were assessment of toxicity, pharmacokinetic determination of RH1 and pharmacodynamic assessment of drug effect through measurement of DNA cross linking in peripheral blood mononuclear cells (PBMCs) and tumour, DTD activity in tumour and NAD(P)H:quinone oxidoreductase 1 (NQO1) polymorphism status. RESULTS: Eighteen patients of World Health Organization performance status of zero to one with advanced refractory solid malignancies were enrolled. MTD was 1430 µg/m(2)/day with reversible bone marrow suppression being dose limiting. Plasma pharmacokinetic analysis showed RH1 is rapidly cleared from blood (t(1/2) = 12.3 min), with AUC increasing proportionately with dose. The comet-X assay demonstrated dose-related increases in DNA cross linking in PBMCs. DNA cross linking was demonstrated in tumours, even with low levels of DTD. Only one patient was homozygous for NQO1 polymorphism precluding any conclusion of its effect. CONCLUSIONS: RH1 was well tolerated with predictable and manageable toxicity. The MTD of 1430 µg/m(2)/day is the dose recommended for phase II trials. The biomarkers of DNA cross linking, DTD activity and NQO1 status have been validated and clinically developed.
Assuntos
Aziridinas/uso terapêutico , Benzoquinonas/uso terapêutico , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neoplasias/tratamento farmacológico , Adulto , Idoso , Aziridinas/farmacocinética , Benzoquinonas/farmacocinética , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , NAD(P)H Desidrogenase (Quinona)/genética , Neoplasias/enzimologia , Neoplasias/patologia , Polimorfismo Genético/genética , Estudos Retrospectivos , Distribuição Tecidual , Resultado do TratamentoRESUMO
Directed enzyme prodrug therapy is an extensive area of research in cancer chemotherapy. Although very promising, the current directed approaches are still hampered by inefficient enzyme expression and tumor targeting. This work investigates the viability of using metal nanoparticles as a novel delivery vehicle for prodrug-activating enzymes. Using genetically incorporated amino acid sequences, a nitroreductase from E. coli was directly immobilized onto a 50 nm gold colloid, as confirmed by gel electrophoresis, DLS, and UV-vis spectroscopy. The resulting conjugates showed excellent stability in changing proton and sodium chloride environments, including PBS at 37 °C. Remarkably, the immobilized nitroreductase retained more than 99% activity to the CB1954 prodrug without the need for stabilizers. This work provides the foundation for attaching prodrug-activating enzymes to metal nanoparticles for future use in directed enzyme prodrug therapy.
Assuntos
Aziridinas/uso terapêutico , Sistemas de Liberação de Medicamentos , Ouro/química , Neoplasias/tratamento farmacológico , Nitrorredutases/química , Pró-Fármacos/uso terapêutico , Engenharia de Proteínas , Coloides/química , Humanos , Modelos Moleculares , Nitrorredutases/isolamento & purificação , Nitrorredutases/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo , Cloreto de Sódio/químicaRESUMO
We report a phase I/II clinical trial in prostate cancer (PCa) using direct intraprostatic injection of a replication defective adenovirus vector (CTL102) encoding bacterial nitroreductase (NTR) in conjunction with systemic prodrug CB1954. One group of patients with localized PCa scheduled for radical prostatectomy received virus alone, prior to surgery, in a dose escalation to establish safety, tolerability, and NTR expression. A second group with local failure following primary treatment received virus plus prodrug to establish safety and tolerability. Based on acceptable safety data and indications of prostate-specific antigen (PSA) responses, an extended cohort received virus at a single dose level plus prodrug. The vector was well tolerated with minimal side effects, had a short half-life in the circulation, and stimulated a robust antibody response. Immunohistochemistry of resected prostate demonstrated NTR staining in tumor and glandular epithelium at all dose levels [5 x 10(10)-1 x 10(12) virus particles (vp)]. A total of 19 patients received virus plus prodrug and 14 of these had a repeat treatment; minimal toxicity was observed and there was preliminary evidence of change in PSA kinetics, with an increase in the time to 10% PSA progression in 6 out of 18 patients at 6 months.
Assuntos
Adenoviridae/genética , Antineoplásicos/uso terapêutico , Aziridinas/uso terapêutico , Terapia Genética/métodos , Vetores Genéticos/genética , Nitrorredutases/fisiologia , Pró-Fármacos/uso terapêutico , Neoplasias da Próstata/terapia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Nitrorredutases/genética , Neoplasias da Próstata/tratamento farmacológicoRESUMO
The enzyme nitroreductase, NfsB, from Escherichia coli has entered clinical trials for cancer gene therapy with the prodrug CB1954 [5-(aziridin-1-yl)-2,4-dinitrobenzamide]. However, CB1954 is a poor substrate for the enzyme. Previously we made several NfsB mutants that show better activity with CB1954 in a cell-killing assay in E. coli. Here we compare the kinetic parameters of wild-type NfsB with CB1954 to those of the most active single, double, and triple mutants isolated to date. For wild-type NfsB the global kinetic parameters for both k(cat) and K(m) for CB1954 are about 20-fold higher than previously estimated; however, the measured specificity constant, k(cat)/K(m) is the same. All of the mutants are more active with CB1954 than the wild-type enzyme, the most active mutant showing about 100-fold improved specificity constant with CB1954 over the wild-type protein with little effect on k(cat). This enhancement in specificity constants for the mutants is not seen with the antibiotic nitrofurazone as substrate, leading to reversed nitroaromatic substrate selectivity for the double and triple mutants. However, similar enhancements in specificity constants are found with the quinone menadione. Stopped-flow kinetic studies suggest that the rate-determining step of the reaction is likely to be the release of products. The most active mutant is also selective for the 4-nitro group of CB1954, rather than the 2-nitro group, giving the more cytotoxic reduction product. The double and triple mutants should be much more effective enzymes for use with CB1954 in prodrug-activation gene therapy.
Assuntos
Antineoplásicos/metabolismo , Aziridinas/metabolismo , Proteínas de Escherichia coli/metabolismo , Escherichia coli/enzimologia , Mutação , Nitrorredutases/metabolismo , Pró-Fármacos/metabolismo , Anti-Infecciosos/química , Anti-Infecciosos/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Aziridinas/química , Aziridinas/uso terapêutico , Escherichia coli/genética , Proteínas de Escherichia coli/genética , Modelos Moleculares , Estrutura Molecular , Nitrofurazona/química , Nitrofurazona/metabolismo , Nitrorredutases/genética , Pró-Fármacos/química , Pró-Fármacos/uso terapêutico , Estrutura Terciária de Proteína , Vitamina K 3/química , Vitamina K 3/metabolismo , Vitaminas/química , Vitaminas/metabolismoRESUMO
Prodrug activation gene therapy is a developing approach to cancer treatment, whereby prodrug-activating enzymes are expressed in tumour cells. After administration of a non-toxic prodrug, its conversion to cytotoxic metabolites directly kills tumour cells expressing the activating enzyme, whereas the local spread of activated metabolites can kill nearby cells lacking the enzyme (bystander cell killing). One promising combination that has entered clinical trials uses the nitroreductase NfsB from Escherichia coli to activate the prodrug, CB1954, to a potent bifunctional alkylating agent. NfsA, the major E. coli nitroreductase, has greater activity with nitrofuran antibiotics, but it has not been compared in the past with NfsB for the activation of CB1954. We show superior in vitro kinetics of CB1954 activation by NfsA using the NADPH cofactor, and show that the expression of NfsA in bacterial or human cells results in a 3.5- to 8-fold greater sensitivity to CB1954, relative to NfsB. Although NfsB reduces either the 2-NO(2) or 4-NO(2) positions of CB1954 in an equimolar ratio, we show that NfsA preferentially reduces the 2-NO(2) group, which leads to a greater bystander effect with cells expressing NfsA than with NfsB. NfsA is also more effective than NfsB for cell sensitisation to nitrofurans and to a selection of alternative, dinitrobenzamide mustard (DNBM) prodrugs.
Assuntos
Antineoplásicos/uso terapêutico , Aziridinas/uso terapêutico , Proteínas de Escherichia coli/genética , Terapia Genética , Nitrorredutases/genética , Neoplasias Ovarianas/terapia , Pró-Fármacos/uso terapêutico , Adenoviridae/genética , Sobrevivência Celular , Cromatografia Líquida de Alta Pressão , Terapia Combinada , Escherichia coli/genética , Feminino , Vetores Genéticos , Humanos , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia , Células Tumorais CultivadasRESUMO
BACKGROUND: HSV1790 is an oncolytic virus generated by inserting the enzyme nitroreductase (NTR) into the virus HSV1716. NTR converts the prodrug CB1954 into an active alkylating agent. MATERIALS AND METHODS: In vitro, 3T6 cells (non permissive to HSV) were used in order to distinguish between virus-induced cytopathic effect and cell death due to activated prodrug. In vivo, xenograft models were injected with HSV1790 (10(5)-10(9) PFU) with or without CB1954 (max 80mg/kg) and tumor volume recorded regularly. Biodistribution of HSV1790 was determined immunohistochemically and by PCR. RESULTS: HSV1790 + CB1954 in vitro was more effective at killing tumor cells than the virus or the prodrug alone. In vivo, the combination reduced tumor volume and increased survival compared to treatment with HSV1790 or CB1954 alone. Following systemic administration of HSV1790, viral replication was detected in tumors, but not organs. CONCLUSION: HSV1790 + prodrug enhances tumor cell killing in vitro and reduces tumor volume and increases survival in vivo.
Assuntos
Antineoplásicos/uso terapêutico , Aziridinas/uso terapêutico , Herpesvirus Humano 1/patogenicidade , Neoplasias Experimentais/terapia , Vírus Oncolíticos/metabolismo , Pró-Fármacos/uso terapêutico , Animais , Western Blotting , Terapia Combinada , Feminino , Herpes Simples/genética , Herpes Simples/patologia , Herpes Simples/virologia , Herpesvirus Humano 1/genética , Humanos , Técnicas Imunoenzimáticas , Camundongos , Camundongos Nus , Neoplasias Experimentais/genética , Neoplasias Experimentais/virologia , Vírus Oncolíticos/genética , Reação em Cadeia da Polimerase , Pró-Fármacos/farmacocinética , Distribuição Tecidual , Replicação ViralRESUMO
Gene directed enzyme prodrug therapy (GDEPT) of cancer aims to improve the selectivity of chemotherapy by gene transfer, thus enabling target cells to convert nontoxic prodrugs to cytotoxic drugs. A zone of cell kill around gene-modified cells due to transfer of toxic metabolites, known as the bystander effect, leads to tumour regression. Here we discuss the implications of either striving for a strong bystander effect to overcome poor gene transfer, or avoiding the bystander effect to reduce potential systemic effects, with the aid of three successful GDEPT systems. This review concentrates on bystander effects and drug development with regard to these enzyme prodrug combinations, namely herpes simplex virus thymidine kinase (HSV-TK) with ganciclovir (GCV), cytosine deaminase (CD) from bacteria or yeast with 5-fluorocytodine (5-FC), and bacterial nitroreductase (NfsB) with 5-(azaridin-1-yl)-2,4-dinitrobenzamide (CB1954), and their respective derivatives.
Assuntos
Terapia Genética/métodos , Pró-Fármacos/uso terapêutico , Animais , Aziridinas/uso terapêutico , Citosina Desaminase/genética , Citosina Desaminase/fisiologia , Flucitosina/uso terapêutico , Ganciclovir/uso terapêutico , Humanos , Nitrorredutases/genética , Nitrorredutases/fisiologia , Timidina Quinase/genéticaRESUMO
PURPOSE: We studied the safety, tolerability and pharmacokinetics of a single immediate post-transurethral resection intravesical instillation of apaziquone for patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Patients with cTa-T1, G1-G2 urothelial cell carcinoma of the bladder underwent transurethral resection of bladder tumor(s) followed by a single intravesical instillation of apaziquone 4 mg/40 ml for 1 hour within 6 hours of transurethral bladder tumor resection. Adverse events and safety parameters were assessed on days 8 and 15 after transurethral bladder tumor resection. Blood samples were drawn before and during the instillation for pharmacokinetic analyses. The first 10 patients with pTa-T1, G1-G2 nonmuscle invasive bladder cancer were also evaluated by cystoscopy 3 months after treatment to determine mucosal healing. RESULTS: Of 20 patients receiving apaziquone 13 (65%) reported 35 adverse events, mostly grade 1 to 2. Eight patients (40%) reported 13 adverse events related to treatment, in particular dysuria, hematuria, bladder spasm, abdominal pain, asthenia and postoperative urinary retention. Three grade 3 and 1 grade 4 event(s) occurred, but these were considered unrelated to treatment. No other significant clinical changes were observed. Apaziquone and the active metabolite EO5a were not detected with pharmacokinetic analyses at any point of time. After 3 months no evidence of impaired mucosal healing was observed. CONCLUSIONS: A single immediate post-transurethral bladder tumor resection instillation of apaziquone was well tolerated with an expected good safety profile. Apaziquone and its metabolite EO5a were not detected systemically with pharmacokinetic analyses. These results have lead to further study of a single immediate instillation of apaziquone.
Assuntos
Antineoplásicos/uso terapêutico , Aziridinas/uso terapêutico , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/cirurgia , Indolquinonas/uso terapêutico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/cirurgia , Administração Intravesical , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Aziridinas/administração & dosagem , Aziridinas/efeitos adversos , Aziridinas/farmacocinética , Carcinoma de Células de Transição/patologia , Terapia Combinada , Feminino , Humanos , Indolquinonas/administração & dosagem , Indolquinonas/efeitos adversos , Indolquinonas/farmacocinética , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Estudos Prospectivos , Fatores de Tempo , Neoplasias da Bexiga Urinária/patologiaRESUMO
Cancer therapy based on the delivery of enzymes to tumour sites has advanced in several directions since antibody-directed enzyme/prodrug therapy was first described. It has been shown that methoxypolyethylene glycol (MPEG) can be used to deliver enzyme to a variety of solid tumours. MPEG-enzyme conjugates show reduced immunogenicity and may allow repeated treatment with enzymes of bacterial origin. Enzyme delivery to tumours by polymers can be used to convert a low toxicity prodrug to a potent cytotoxic agent. An example of such a prodrug is CB1954, which can be activated by a human enzyme in the presence of a cosubstrate. Tumour-located enzymes can also be used in conjunction with a combination of antimetabolites and rescue agents. The rescue agent protects normal tissue but is degraded at cancer sites by the enzyme, thus deprotecting the tumour and allowing prolonged antimetabolite action.
Assuntos
Antineoplásicos/uso terapêutico , Terapia Enzimática , Neoplasias/tratamento farmacológico , Pró-Fármacos/uso terapêutico , Aziridinas/uso terapêutico , Portadores de Fármacos/uso terapêutico , Humanos , Imunoconjugados/uso terapêutico , Polietilenoglicóis/uso terapêutico , Pró-Fármacos/metabolismo , gama-Glutamil Hidrolase/uso terapêuticoRESUMO
During the past decade, the search for an effective system for the selective delivery of high therapeutic doses of anti-cancer agents to tumours has explored a variety of ingenious and increasingly complex biological systems. These systems are most often based on gene therapy and use viral vectors as the delivery vehicle. Invariably, such systems have been found wanting with respect to a lack of tumour specificity, poor levels of transgene expression and inefficient distribution of the vector throughout the tumour mass. By contrast, the ability of intravenously injected clostridial spores to infiltrate, then selectively germinate in, the hypoxic regions of solid tumours seems to be a totally natural phenomenon, which requires no fundamental alterations and is exquisitely specific.
Assuntos
Antineoplásicos/uso terapêutico , Clostridium , Sistemas de Liberação de Medicamentos/métodos , Neoplasias/terapia , Esporos Bacterianos , Animais , Aziridinas/uso terapêutico , Carcinoma/microbiologia , Carcinoma/terapia , Clostridium/enzimologia , Clostridium/genética , Clostridium/crescimento & desenvolvimento , Citosina Desaminase/genética , Humanos , Camundongos , Neoplasias/microbiologia , Nitrorredutases/genética , Pró-Fármacos/uso terapêutico , Xantonas/uso terapêuticoRESUMO
EO9 (apaziquone) is a novel, promising anticancer agent, which is currently being investigated for the intravesical treatment of bladder cancer. EO9 contains a highly reactive aziridine ring in its structure that limits its chemical stability in acidic aqueous solutions. The stability of the pharmaceutically formulated EO9 in human urine, including the effects of several parameters such as temperature, buffer strength and pH have been investigated. Urine extracts were analyzed by high-performance liquid chromatography coupled to electrospray tandem mass spectrometry (HPLC-MS/MS) using a TurboIonspray interface and positive-ion multiple reaction monitoring. EO9 was unstable in urine at 43 degrees C during the instillation for longer than 1 h. However, the drug was stable in human urine for 3 h at 37 degrees C. EO9 is stable in urine stabilized with TRIS buffer (pH 9.0; 5 mM) for up to three freeze/thaw cycles at -20 and -70 degrees C and 3 months of storage at -70 degrees C. The results also illustrated that with the lower pH in urine, EO9 became more unstable. Furthermore, a new degradation product of EO9 was discovered and successfully identified as EO9-Cl. The outcomes of these stability experiments will be implemented to insure proper sample handling at the clinical sites, transport, storage, and sample handling during analysis in the forthcoming preclinical studies of EO9 in superficial bladder cancer, supported by bioanalysis and pharmacokinetic monitoring.
Assuntos
Antineoplásicos/urina , Aziridinas/urina , Indolquinonas/urina , Neoplasias da Bexiga Urinária/tratamento farmacológico , Antineoplásicos/uso terapêutico , Aziridinas/uso terapêutico , Soluções Tampão , Calibragem , Cromatografia Líquida de Alta Pressão , Humanos , Concentração de Íons de Hidrogênio , Indolquinonas/uso terapêutico , Espectrometria de Massas , Padrões de Referência , Manejo de Espécimes , TemperaturaRESUMO
Currently available cancer chemotherapeutic agents have been designed to exploit subtle differences in proliferation and biochemistry that are known to exist between host and malignant cells. However, chemotherapeutic agents may also be used to exploit physiological differences between cancer and normal tissue. The present study was conducted to determine whether the reduction in blood flow to the tumor (and thus oxygen delivery) induced by the vasodilator hydralazine would increase the cytotoxicity of drugs known to be more toxic in regions of reduced oxygenation. Results obtained with three murine tumor models clearly demonstrate that hydralazine potentiates the tumor cytotoxicity of such agents to a greater extent than it does their systemic toxicity. This study indicates a potential strategy for increasing the efficacy of certain cancer chemotherapeutic agents in solid tumors.
Assuntos
Hidralazina/farmacologia , Neoplasias Experimentais/irrigação sanguínea , Animais , Antineoplásicos/uso terapêutico , Aziridinas/uso terapêutico , Sinergismo Farmacológico , Feminino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Misonidazol/análogos & derivados , Misonidazol/uso terapêutico , Mitomicinas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
BACKGROUND: A novel bioreductive alkylating indoloquinone compound, E09 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)- prop-F128b-en-alpha-ol], has been shown to have distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, but no notable bone marrow toxicity in preclinical models. PURPOSE: A phase I study was carried out to determine the toxicity, maximum tolerated dose (MTD), pharmacology, and antitumor response of E09. METHODS: E09 was administered as a 5-minute intravenous infusion once every 3 weeks to 32 patients with solid tumors. The starting dose of 2.7 mg/m2 was one tenth of the mouse equivalent of lethal dose to 10% of animals (MELD10). Dose was escalated by 100% until the area under the curve (AUC) at the MELD10 was reached, following a Fibonacci-like schedule. The pharmacokinetics of E09 and its metabolite E05A with an open aziridine ring was determined using a new high-pressure liquid chromatographic method and noncompartmental calculation of kinetic parameters. The sigmoid Emax model was used to fit pharmacokinetic parameters to toxicity. The renal function and proteinuria were quantitated and were further evaluated by determining renal clearance ratios of immunoglobulin G (IgG) to albumin and pancreatic amylase to salivary amylase. RESULTS: The 32 patients were treated with a total of 85 assessable courses of E09. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. All symptoms were reversible on day 15 except in two patients, who developed acute renal failure. The ratios of IgG to albumin and pancreatic amylase to salivary amylase suggested a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The pharmacokinetics of E09 showed its rapid elimination from the central compartment but with wide interpatient variation in the overall disposition of the drug. Total plasma clearance of E09 ranged from 3.2 to 24 L/min. The AUC of E09 was linearly related to the administered dose. The relationship between the AUC and proteinuria was best fitted by the sigmoid Emax model (r = .98). In two patients with adenocarcinoma of unknown primary site and in a third patient with bile duct cancer, a partial response was observed. CONCLUSIONS: The MTD of E09 was determined to be 27 mg/m2. The standard approach of drug administration is considered unsuitable because of potential renal toxicity and wide variability in the pharmacokinetics of E09. Individual dose adjustments based on plasma concentration measurements are recommended to combine maximally achievable exposure with tolerable toxicity.
Assuntos
Antineoplásicos/uso terapêutico , Aziridinas/uso terapêutico , Indolquinonas , Indóis/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Aziridinas/efeitos adversos , Aziridinas/farmacocinética , Aziridinas/farmacologia , Feminino , Humanos , Indóis/efeitos adversos , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Proteinúria/induzido quimicamenteRESUMO
The biological half-lives and decay rate constants under the conditions of a human brain tumor clonogenic cell assay were determined for six clinically used anticancer agents. The agents studied were: 1,3-bis(2-chloroethyl)-1-nitrosourea; 3-(2-chloroethyl-3-nitrosoureido-2-deoxy-D-glucopyranose; cis-diaminedichloroplatinum(II); 2,5-diaziridinyl-3,6-bis-(carboethoxyamino)-1,4-benzoquinone; 4-demethylepipodophylotoxin-D-thylidene glucoside; and 9-hydroxy-2-N-methylellipticine. In vitro decay of all six drugs was found to be according to first order kinetics. The half-lives of two drugs, namely, 1,3-bis(2-chloroethyl-1-nitrosourea and 3-(2-chloroethyl-3-nitrosoureido-2-deoxy-D-glucopyranose under the human tumor clonogenic cell assay (HTCA) conditions were found to be similar to their terminal in vivo half-lives in humans. For the other drugs, however, there was a very large difference between their in vitro and in vivo pharmacokinetics. In the case of 2,5-diaziridinyl-3,6-bis(carboethoxyamine)-1,4-benzoquinone, we observed about an 80-fold difference between its in vitro half-life of 40.76 h and its in vivo terminal half-life of 0.52 h. We describe the principles upon which these data can be used to design clinically more relevant in vitro drug exposure protocols in HTCAs. Since, generally, tumor cells are exposed to drugs in the HTCA either continuously or for a specified duration, e.g., 1 or 2 h, we computed the initial in vitro drug concentrations to which tumor cells should be exposed such that the resulting in vitro (c X t) after a 2-h or a continuous exposure will be within clinically achievable levels. The application of these in vivo and in vitro pharmacokinetic principles will provide for more physiological testing of patient tumor cell sensitivity to anticancer drugs in the HTCA, and is likely to result in lower rates of false positive responses in clinical trials using clonogenic cell assays.
Assuntos
Antineoplásicos/metabolismo , Benzoquinonas , Neoplasias Encefálicas/metabolismo , Aziridinas/uso terapêutico , Bioensaio , Carmustina/uso terapêutico , Linhagem Celular , Cisplatino/uso terapêutico , Células Clonais , Relação Dose-Resposta a Droga , Elipticinas/uso terapêutico , Glioma/metabolismo , Meia-Vida , Humanos , Matemática , Estreptozocina/análogos & derivados , Estreptozocina/uso terapêutico , Teniposídeo/uso terapêuticoRESUMO
Aziridinylbenzoquinone is a quinone compound capable of penetrating the central nervous system. It has demonstrated activity against both intracranial and i.p. murine tumors and human tumor xenographs. We have conducted a Phase I trial of aziridinylbenzoquinone in 60 children with advanced cancer who were refractory to conventional therapy. The drug was given by slow i.v. push on a daily schedule for 5 days every 3 to 4 weeks. The dose range explored included 6 dose levels, ranging from 6 to 12 mg/sq m daily for 5 days in patients with solid tumors and leukemia, and in patients with leukemia, 20, 25, and 30 mg/sq m daily for 5 days. Myelosuppression was the dose-limiting side effect. In patients with solid tumor the highest dose studied was 12 mg/sq m, and the median nadir white blood cell and platelet counts were 0.7 X 10(3) and 6.0 X 10(3)/microliter on Days 17 and 22, respectively. The median recovery day for white blood cells was 39. There may be some evidence of cumulative toxicity with prolonged thrombocytopenia. Other side effects were mild nausea, vomiting, and mucositis. Elevations in liver enzymes and bilirubin were transient and dose dependent, occurring 3 to 4 weeks after drug administration. Of the 34 children with solid tumors, 33 were evaluable for hematopoietic toxicity, 3 were early deaths, and 31 receiving a total of 55 courses were evaluable for therapeutic response. Partial responses lasting 3 weeks to 6 months were seen in the 4 patients with Hodgkin's disease, and in a child with a metastatic spinal cord ependymoma. Fifty-two courses were given to 9 patients with acute lymphocytic leukemia and 17 with acute nonlymphoblastic leukemia. Of the 15 patients with acute nonlymphoblastic leukemia treated at doses greater than or equal to 25 mg/sq m/day for 5 days there was one early death and there were 2 M1 (less than or equal to 5% blasts with normal cellularity), 3 M2A (6 to 15% blasts), and 2 M2B (16 to 39% blasts) bone marrow responses lasting 1 to 3.5 months. Aziridinylbenzoquinone demonstrated activity against acute nonlymphocytic leukemia with maximal tolerated doses of 30 mg/sq m daily for 5 days. Its effect in Hodgkin's disease is encouraging; however, further study will be required to determine its efficacy in central nervous system cancers. Recommended doses for Phase II studies, using daily schedule for 5 days in children with solid tumors, is 9 mg/sq m, and in children with leukemia, it is 25 mg/sq m.