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Journal of Clinical Neuroscience :... Mar 2001An important role for pre-clinical models of medulloblastoma/primitive neuroectodermal tumour (MB/PNET) is inhibited by the limitations of conventional...
An important role for pre-clinical models of medulloblastoma/primitive neuroectodermal tumour (MB/PNET) is inhibited by the limitations of conventional heterotransplantation. Nine cohorts of MB/PNET were studied for subcutaneous engraftment in nude mice by both conventional and Matrigel supplemented methods. While no subcutaneous tumours resulted from 63 conventional attempts, an aggregate 41 xenografts from 72 injections (57%) were produced when Matrigel was added to the cell suspension. In subsequent passage, engraftment rate approached 100%. To study the response to chemotherapeutic agents in the model, a total of 221 tumours in 3 cohorts were treated using one of the following: cisplatin, carboplatin, vincristine, cyclophosphamide, diaziquone, or saline control. While all agents demonstrated statistically significant activity, cyclophosphamide proved to be particularly effective. The potential applications of this xenograft model in the biologic as well as therapeutic study of MB/PNET deserve continuing investigation.
Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Antineoplastic Agents, Phytogenic; Aziridines; Benzoquinones; Biocompatible Materials; Carboplatin; Cerebellar Neoplasms; Cisplatin; Collagen; Cyclophosphamide; Drug Combinations; Immunophenotyping; Laminin; Medulloblastoma; Mice; Mice, Inbred BALB C; Mice, Nude; Neuroectodermal Tumors, Primitive; Proteoglycans; Treatment Outcome; Vincristine; Xenograft Model Antitumor Assays
PubMed: 11484666
DOI: 10.1054/jocn.2000.0734 -
Drug Safety Jan 2001Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Renal dysfunction can be categorised as prerenal uraemia, intrinsic damage or postrenal uraemia... (Review)
Review
Nephrotoxicity is an inherent adverse effect of certain anticancer drugs. Renal dysfunction can be categorised as prerenal uraemia, intrinsic damage or postrenal uraemia according to the underlying pathophysiological process. Renal hypoperfusion promulgates prerenal uraemia. Intrinsic renal damage results from prolonged hypoperfusion, exposure to exogenous or endogenous nephrotoxins, renotubular precipitation of xenobiotics or endogenous compounds, renovascular obstruction, glomerular disease, renal microvascular damage or disease, and tubulointerstitial damage or disease. Postrenal uraemia is a consequence of clinically significant urinary tract obstruction. Clinical signs of nephrotoxicity and methods used to assess renal function are discussed. Mechanisms of chemotherapy-induced renal dysfunction generally include damage to vasculature or structures of the kidneys, haemolytic uraemic syndrome and prerenal perfusion deficits. Patients with cancer are frequently at risk of renal impairment secondary to disease-related and iatrogenic causes. This article reviews the incidence, presentation, prevention and management of anticancer drug-induced renal dysfunction. Dose-related nephrotoxicity subsequent to administration of certain chloroethylnitrosourea compounds (carmustine, semustine and streptozocin) is commonly heralded by increased serum creatinine levels, uraemia and proteinuria. Additional signs of streptozocin-induced nephrotoxicity include hypophosphataemia, hypokalaemia, hypouricaemia, renal tubular acidosis, glucosuria, aceturia and aminoaciduria. Cisplatin and carboplatin cause dose-related renal dysfunction. In addition to increased serum creatinine levels and uraemia, electrolyte abnormalities, such as hypomagnesaemia and hypokalaemia, are commonly reported adverse effects. Rarely, cisplatin has been implicated as the underlying cause of haemolytic uraemic syndrome. Pharmaceutical antidotes to cisplatin-induced nephrotoxicity include amifostine, sodium thiosulfate and diethyldithiocarbamate. Dose- and age-related proximal tubular damage is an adverse effect of ifosfamide. In addition to renal wasting of electrolytes, glucose and amino acids, Fanconi syndrome, rickets and osteomalacia have occurred with ifosfamide treatment. High dose azacitidine causes renal dysfunction manifested by tubular acidosis, polyuria and increased urinary excretion of electrolytes, glucose and amino acids. Haemolytic uraemia is a rare adverse effect of gemcitabine. Methotrexate can cause increased serum creatinine levels, uraemia and haematuria. Acute renal failure is reported following administration of high dose methotrexate. Urinary alkalisation and hydration confer protection against methotrexate-induced renal dysfunction. Dose-related nephrotoxicity, including acute renal failure, are reported subsequent to treatment with pentostatin and diaziquone. Acute renal failure is a rare adverse effect of treatment with interferon-alpha. Haemolytic uraemic syndrome occurs with mitomycin administration. A mortality rate of 50 to 100% is reported in patients developing mitomycin-induced haemolytic uraemic syndrome. Capillary leak syndrome occurring with aldesleukin therapy can cause renal dysfunction. Infusion-related hypotension during infusion of high dose carmustine can precipitate renal dysfunction.
Topics: Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Aziridines; Benzoquinones; Humans; Interferon-alpha; Renal Insufficiency
PubMed: 11219485
DOI: 10.2165/00002018-200124010-00003 -
Statistics in Medicine Jan 2001This paper considers several permutation tests for treatment-by-centre interaction in multi-centre clinical trials in which the endpoint is survival time subject to... (Comparative Study)
Comparative Study
This paper considers several permutation tests for treatment-by-centre interaction in multi-centre clinical trials in which the endpoint is survival time subject to censoring. Some of the tests are based on existing tests and some are new. To evaluate and compare the tests with respect to power under different conditions, we generated survival times and censoring times through simulation. We used special methodology to handle the unusual problems that arise in power simulations when the tests under study are permutation tests. Different conditions yielded different interaction tests as the best performers. Although one test gave comparatively good power under almost all conditions, some of the other tests also appear to be useful. For the sample sizes and configurations in the simulations, power is generally low; thus it may not be possible to detect interaction reliably when it exists, a finding in agreement with the known low power for interaction tests in general.
Topics: Aged; Antineoplastic Agents, Alkylating; Aziridines; Benzoquinones; Brain Neoplasms; Carmustine; Computer Simulation; Glioma; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Leukemia, Myeloid; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Remission Induction; Statistics as Topic
PubMed: 11169597
DOI: 10.1002/1097-0258(20010130)20:2<193::aid-sim651>3.0.co;2-# -
Frontiers in Bioscience : a Journal and... Nov 2000Aziridinyl quinones can be activated by cellular reductases eg. DT-diaphorase and cytochrome P450 reductase to form highly reactive DNA alkylating agents. The mechanisms... (Review)
Review
Aziridinyl quinones can be activated by cellular reductases eg. DT-diaphorase and cytochrome P450 reductase to form highly reactive DNA alkylating agents. The mechanisms by which this activation and alkylation take place are many and varied. Using clinically relevant and experimental agents this review will describe many of these mechanisms. The agents discussed are Mitomycin C, EO9 and analogues, diaziridinylbenzoquinones and the pyrrolo[1, 2-alpha]benzimidazolequinones.
Topics: Alkylation; Antineoplastic Agents, Alkylating; Aziridines; Benzimidazoles; Benzoquinones; Carbazilquinone; DNA; Doxorubicin; Humans; Indolequinones; Indoles; Mitomycin; Molecular Structure; Oxidation-Reduction; Quinones; Structure-Activity Relationship
PubMed: 11056081
DOI: 10.2741/hargreav -
Frontiers in Bioscience : a Journal and... Nov 2000Quinone-containing alkylating agents are a class of chemical agents that have received considerable interest as anticancer drugs. These agents contain a quinone moiety... (Review)
Review
Quinone-containing alkylating agents are a class of chemical agents that have received considerable interest as anticancer drugs. These agents contain a quinone moiety that can be reduced and an alkylating group that can form covalent bonds with a variety of cellular components. The oxidation state of the quinone element can modulate the activity of the alkylating element, and reduction of the quinone is required for activation of the alkylating activity of many of these agents. The quinone element may also contribute to the cytotoxic activity of quinone-containing alkylating agents through the formation of reactive oxygen species during redox cycling. The natural product, mitomycin C, has been the most widely used quinone-containing alkylating agent in the clinic, but other quinone-containing alkylating agents like porfiromycin, diaziquone, carbazilquinone, triaziquone and EO9 have also been used in the clinic for the treatment of cancer. In addition, many other quinone-containing alkylating agents have been tested in preclinical studies and the development of new agents is being actively pursued. This chapter describes the current and past clinical uses of these agents in the treatment of cancer and discusses new agents that are currently in clinical trials.
Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Aziridines; Benzoquinones; Clinical Trials as Topic; Drug Evaluation, Preclinical; History, 20th Century; Humans; Indolequinones; Indoles; Mitomycin; Neoplasms; Quinones; Structure-Activity Relationship
PubMed: 11056078
DOI: 10.2741/begleit -
Molecular Pharmacology Nov 2000Many tumors overexpress the NQO1 gene, which encodes DT-diaphorase (NADPH:quinone oxidoreductase; EC 1.6.99.2). This obligate two-electron reductase deactivates toxins...
Establishment of an isogenic human colon tumor model for NQO1 gene expression: application to investigate the role of DT-diaphorase in bioreductive drug activation in vitro and in vivo.
Many tumors overexpress the NQO1 gene, which encodes DT-diaphorase (NADPH:quinone oxidoreductase; EC 1.6.99.2). This obligate two-electron reductase deactivates toxins and activates bioreductive anticancer drugs. We describe the establishment of an isogenic human tumor cell model for DT-diaphorase expression. An expression vector was used in which the human elongation factor 1alpha promoter produces a bicistronic message containing the genes for human NQO1 and puromycin resistance. This was transfected into the human colon BE tumor line, which has a disabling point mutation in NQO1. Two clones, BE2 and BE5, were selected that were shown by immunoblotting and enzyme activity to stably express high levels of DT-diaphorase. Drug response was determined using 96-h exposures compared with the BE vector control. Functional validation of the isogenic model was provided by the much greater sensitivity of the NQO1-transfected cells to the known DT-diaphorase substrates and bioreductive agents streptonigrin (113- to 132-fold) and indoloquinone EO9 (17- to 25-fold) and the inhibition of this potentiation by the DT-diaphorase inhibitor dicoumarol. A lower degree of potentiation was seen with the clinically used agent mitomycin C (6- to 7-fold) and the EO9 analogs, EO7 and EO2, that are poorer substrates for DT-diaphorase (5- to 8-fold and 2- to 3-fold potentiation, respectively), and there was no potentiation or protection with menadione and tirapazamine. Exposure time-dependent potentiation was seen with the diaziquone analogs methyl-diaziquone and RH1 [2, 5-diaziridinyl-3-(hydroxymethyl)-6-methyl-1,4-benzoquinone], the latter being an agent in preclinical development. In contrast to the in vitro potentiation, there was no difference in the response to mitomycin C when BE2 and BE vector control were treated as tumor xenografts in vivo. This isogenic model should be valuable for mechanistic studies and bioreductive drug development.
Topics: Animals; Antibiotics, Antineoplastic; Colonic Neoplasms; Disease Models, Animal; Gene Expression; HT29 Cells; Humans; Mice; Mice, Nude; Mitomycin; Models, Biological; NAD(P)H Dehydrogenase (Quinone); Neoplasm Transplantation; Reducing Agents; Streptonigrin; Transplantation, Heterologous; Treatment Outcome; Tumor Cells, Cultured
PubMed: 11040064
DOI: 10.1124/mol.58.5.1146 -
Free Radical Biology & Medicine Sep 2000Quantifying oxygen radicals that arise during the redox cycling of quinone-containing anticancer agents such as diaziquone (AZQ) has been difficult, as has been their...
Quantifying oxygen radicals that arise during the redox cycling of quinone-containing anticancer agents such as diaziquone (AZQ) has been difficult, as has been their detection at low drug concentrations. This is due to the fact that EPR spin trapping, the method most often used for *OH detection, requires the use of high drug concentrations. Using a new highly sensitive technique that employs a fluorescamine-derivatized nitroxide, we show that low levels of NADPH-cytochrome P450 reductase (4.25 microg/ml) catalyze the production of hydroxyl radicals at very low, clinically relevant AZQ concentrations. Thus, at this enzyme concentration, we were able to detect a rate of 0.10 nM s(-1) hydroxyl radical production by 5 microM AZQ, a clinically relevant concentration. The Michaelis-Menten constants for AZQ-mediated hydroxyl radical production are: K(M) = 10.7 +/- 1.4 microM, and V(max) = 5.2 +/- 0.9 x 10(-8) M s(-1) (mg protein)(-1). Experiments employing catalase, superoxide dismutase, and NADPH-cytochrome P450 reductase, confirm the previously deduced conclusions from high drug concentrations, that is, that at low concentrations, AZQ acts to shuttle reducing equivalents from the enzyme to oxygen, thus generating the redox cycle. The data presented here suggest that the levels and locations of redox active metal ions may be the principal controlling factor in the pathway of AZQ activity that involves oxidative stress.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Chromatography, High Pressure Liquid; Dimethyl Sulfoxide; Electron Spin Resonance Spectroscopy; Free Radicals; Hydroxyl Radical; Iron; Kinetics; Liver; Molecular Structure; NADPH-Ferrihemoprotein Reductase; Oxidation-Reduction; Oxygen; Rats; Superoxide Dismutase
PubMed: 11025198
DOI: 10.1016/s0891-5849(00)00402-0 -
Journal of Clinical Oncology : Official... Dec 1999To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
To examine the effect of single compared with repetitive (at least three) cycles of high-dose cytarabine after induction therapy for patients with acute myeloid leukemia (AML) who have the t(8;21)(q22;q22) karyotype.
PATIENTS AND METHODS
Patients entered onto the study had AML and t(8;21) and attained a complete remission on four successive Cancer and Leukemia Group B studies. In these studies, either > or = three cycles of high-dose cytarabine or one cycle of high-dose cytarabine was administered, followed by sequential cyclophosphamide/etoposide and mitoxantrone/diaziquone with or without filgrastim support. Outcomes of these two groups of t(8;21) patients were compared.
RESULTS
A total of 50 patients with centrally reviewed AML and t(8;21) were assigned to receive one (n = 29) or > or = three cycles (n = 21) of high-dose cytarabine as postinduction therapy. The clinical features of these two groups of patients were similar. Initial remission duration for t(8;21) patients assigned to one cycle of high-dose cytarabine was significantly inferior (P =.03), with 62% of patients experiencing relapse with a median failure-free survival of 10.5 months, compared with the group of patients who received > or = three cycles, in which only 19% experienced relapse and failure-free survival is estimated to be greater than 35 months. Furthermore, overall survival was also significantly compromised (P =.04) in patients assigned to one cycle of high-dose cytarabine, with 59% having died as a consequence of AML, compared with 24% of those who received > or = three cycles of high-dose cytarabine.
CONCLUSION
These data demonstrate that failure-free survival and overall survival of patients with t(8;21)(q22;q22) may be compromised by treatment approaches that do not include sequential high-dose cytarabine therapy.
Topics: Adolescent; Adult; Aged; Antimetabolites, Antineoplastic; Chromosomes, Human, Pair 21; Chromosomes, Human, Pair 8; Cytarabine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Prospective Studies; Survival Analysis; Translocation, Genetic
PubMed: 10577848
DOI: 10.1200/JCO.1999.17.12.3767 -
Chemical Research in Toxicology Nov 1999The effect of quinone anti-cancer compounds, 3,6-diaziridinyl-2, 5-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone or AZQ) and 3,...
The effect of quinone anti-cancer compounds, 3,6-diaziridinyl-2, 5-bis(carboethoxyamino)-1,4-benzoquinone (diaziquone or AZQ) and 3, 6-dihydro-2,5-bis(aziridinyl)-1,4-benzoquinone (DZQ), on the production of hydroxyl radical ((*)OH) in a series of mouse epidermal cell lines was examined using a new, highly sensitive method that employs a fluorescamine-derivatized nitroxide probe. Cell lines that were examined included the mouse epidermal cell line, JB6 clone 41, and JB6 cells transfected with the human Cu-Zn superoxide dismutase (SOD) genes (SOD3 and SOD15) and human catalase (CAT) genes (CAT13 and CAT10). Bioreduction of the nitroxide probe by these cell lines was insignificant at the cell densities employed in these experiments, and thus did not interfere with the (*)OH measurements. In the presence of low concentrations of AZQ or DZQ (20-200 microM), (*)OH production rates were highest in the JB6 cells, intermediate in the SOD-transfected cells, and lowest in the CAT-transfected cells, illustrating that both superoxide and hydrogen peroxide are involved in the production of (*)OH in these systems. Further experiments in which the addition of exogenous SOD and CAT was employed, as well as measurements of probe incorporation into the cells, indicated that this probe can cross cell membranes and detect (*)OH generated intracellularly. In the presence of 100 microM diethylenetriaminepentaacetic acid (DTPA), the rate of (*)OH production in the presence of 100 microM AZQ is approximately 4.7 x 10(4) molecules s(-)(1) cell(-)(1); as much as 45% of this production appears to originate within the cells. This new method should be broadly applicable to the rapid screening of compounds or treatments thought to induce oxidative stress in mammalian cells.
Topics: Animals; Antineoplastic Agents; Catalase; Cell Line; Epidermal Cells; Epidermis; Extracellular Space; Humans; Hydroxyl Radical; Kinetics; Mice; Oxidation-Reduction; Quinones; Superoxide Dismutase; Transfection
PubMed: 10563829
DOI: 10.1021/tx990095m -
Journal of Cancer Research and Clinical... 1999The disappointing results of chemotherapy in glioblastoma might be caused by the choices of agents, which mostly include nitrosurea. We compared the in vitro efficacy of... (Meta-Analysis)
Meta-Analysis
PURPOSE
The disappointing results of chemotherapy in glioblastoma might be caused by the choices of agents, which mostly include nitrosurea. We compared the in vitro efficacy of chemotherapeutic agents, developing a method to summarize published data.
METHOD
Between 1966 and 1995 chemotherapy in glioma cells was reported in 1643 articles. Efficacy was mostly described by the drug concentration that killed 50% of the cells (LC50). It was measured with various cell-culture techniques, of which a colorimetric test [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltrazolium bromide] was mostly used. We calculated factors from these data to transform results to LC50 values as if the colorimetric test was used in all of them. This allowed data from all publications to be summarized in a new type of meta analysis.
RESULTS
The most important agents and the average LC50 values (mg/l) were actinomycin-D 0.042, vincristine 0.075, mitoxantrone 0.12, vinblastine 0.21, doxorubicin 0.29, diaziquone 0.76, cisplatin 1.1, methotrexate 1.1, cytasine arabinoside 1.59, 5-flurouracil 2.33, bleomycin 18.6, carboplatin 29.8, carmustine 37.0, nimustine 48.9, and lomustine 76.7. The most resistant cell was SNB56, followed with increasing sensitivity by SF128 and A172, and primary cultures P497, SF210, U87MG, SF126, 9L, P540, U251MG, HU62, C6. The complete list of original data is available upon request.
CONCLUSION
The efficacy of nitrosourea in vitro is low.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Glioma; Humans; Lethal Dose 50; Models, Statistical; Tumor Cells, Cultured
PubMed: 10480340
DOI: 10.1007/s004320050305