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Journal of Neurosurgery Feb 1994In a pilot study, two groups of patients with malignant glioma underwent sequential neuropsychological evaluations after successful tumor treatment. Group 1 included...
In a pilot study, two groups of patients with malignant glioma underwent sequential neuropsychological evaluations after successful tumor treatment. Group 1 included nine patients treated from 1981 to 1985; all patients received irradiation and eight underwent chemotherapy. The baseline neuropsychological assessment was performed 1 to 63 months after tumor diagnosis, with follow-up evaluations at irregular intervals over the next 3 to 7 years. Six patients in Group 1 exhibited impairment on most measures at baseline; subsequently, two patients developed profound cognitive impairment. Initially, three patients functioned in the average range on most tasks; thereafter, two deteriorated on one measure each. Group 2 was ascertained prospectively and included 16 patients treated from 1985 to 1987, all of whom received irradiation and chemotherapy. The first evaluation was performed 18 months after diagnosis, then every 6 months for 2 years, and then yearly. Compared to a control group, those in Group 2 had significant cognitive impairment at baseline. Cognitive performance did not change over the next 12 months in 10 patients who remained free of tumor, but within 2 years of baseline testing, deterioration on specific tasks was evident in two of seven disease-free survivors. When last tested, five of six disease-free survivors had deteriorated on one or more measures. Unlike Group 1, severe global cognitive impairment was not seen, perhaps because Group 2 was followed for a shorter time. Verbal and nonverbal composite scores derived from intelligence quotient (IQ) tests showed less impairment at baseline than did other measures and were more likely to remain stable subsequently. Verbal memory and sustained attention were the most impaired at baseline, and verbal learning and flexibility in thinking showed the greatest tendency to decline over time. Cognitive functioning in survivors of high-grade glioma is best measured and monitored by tests that probe a broader spectrum of abilities than IQ. Neuropsychological measures used in this analysis lacked sensitivity at the lower end of the impaired range. Future studies should use tests better able to discern cognitive differences at low performance levels. Based on this experience, the authors conclude that most long-term survivors of high-grade glioma will have significant cognitive difficulties, usually evident by the first assessment; some patients will develop profound impairment years later, and few are capable of fully independent living.
Topics: Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Brain Neoplasms; Carmustine; Cognition; Female; Glioma; Humans; Male; Middle Aged; Neuropsychological Tests; Pilot Projects
PubMed: 8283263
DOI: 10.3171/jns.1994.80.2.0247 -
Journal of Neuro-oncology 1994A two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment of de novo or recurrent primary brain tumors. An additional... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
A two-arm randomized clinical trial was performed to determine the efficacy of PCNU and AZQ in the treatment of de novo or recurrent primary brain tumors. An additional objective was to gather information on the administration and toxicity of these compounds, supplementing that obtained previously in phase I/II studies.
METHODS
During 1982 and 1983 the Brain Tumor Study Group randomized 152 adult patients with primary brain tumors to receive PCNU 75-100 mg/m2 intravenously (IV) every 8 weeks or AZQ 15 mg/m2 IV once a week for 4 weeks, every 6-8 weeks. All patients who had not received 'full dose' radiotherapy before randomization received it concurrently with the first course of protocol chemotherapy. The data were analyzed for the total randomized population (RP), and for 130 patients in the valid study group (VSG) formed by excluding 22 patients for whom the histologic diagnosis was not documented by central review.
RESULTS
Median survival times were 11.0 months for the PCNU group and 8.4 months for the AZQ group. The difference in survival curves was statistically significant for the RP (p = 0.01) and the VSG (p = 0.02). Life-table analysis of the VSG showed estimated 2-year survivals of 34% for PCNU and 11% for AZQ. The advantage of PCNU remained significant (p = 0.006) after adjustment for histopathologic category, age, initial performance status, and interval from initial reported surgery. Myelosuppression was the principal toxicity in both groups.
Topics: Antineoplastic Agents; Aziridines; Benzoquinones; Brain Neoplasms; Child; Humans; Middle Aged; Nitrosourea Compounds; Prospective Studies; Recurrence; Survival Analysis
PubMed: 7714551
DOI: 10.1007/BF01058355 -
Journal of Neuro-oncology 1994The rat 9L gliosarcoma brain tumor model has been used for more than thirty years to investigate a variety of potential therapeutic agents, combinations, schedules, and...
The rat 9L gliosarcoma brain tumor model has been used for more than thirty years to investigate a variety of potential therapeutic agents, combinations, schedules, and approaches that might be applicable to the management of high-grade malignant brain tumors in man. When tumor cells are implanted intracerebrally, a solid tumor grows until its mass results in the death of the animal, typically between 20 and 30 days postinoculation. Radiation therapy (either single or fractionated doses) is effective at prolonging survival in a dose-dependent manner. Numerous cancer chemotherapeutic agents, by a variety of doses, schedules, and routes of delivery, have demonstrated therapeutic efficacy in the 9L model. The combination of radiation and agents such as AZQ, BCNU, bleomycin, and cis-platinum has resulted in prolongation of survival that is significantly better than either agent used alone, without exceeding the tolerance of critical normal tissues. These pre-clinical data suggest that combining standard fractionated radiation therapy with appropriate concomitant cytotoxic chemotherapeutic agents might benefit patients with high-grade brain tumors.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Bleomycin; Brain Neoplasms; Carmustine; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Disease Models, Animal; Dose-Response Relationship, Radiation; Gliosarcoma; Male; Organometallic Compounds; Rats; Rats, Inbred F344; Spiro Compounds; Vincristine
PubMed: 7528789
DOI: 10.1007/BF01052721 -
Chemico-biological Interactions Sep 1993Electron paramagnetic resonance (EPR/ESR) spin trapping studies with DMPO revealed that purified rat liver NAD(P)H (quinone-acceptor) oxidoreductase (QAO) mediated... (Comparative Study)
Comparative Study
Electron paramagnetic resonance (EPR/ESR) spin trapping studies with DMPO revealed that purified rat liver NAD(P)H (quinone-acceptor) oxidoreductase (QAO) mediated hydroxyl radical formation by a diverse range of quinone-based antitumour agents. However, when MCF-7 S9 cell fraction was the source of QAO, EPR studies distinguished four different interactions by these agents and QAO with respect to hydroxyl radical formation: (i) hydroxyl radical formation by diaziquone (AZQ), menadione, 1AQ; 1,5AQ and 1,8AQ was mediated entirely or partially by QAO in MCF-7 S9 fraction; (ii) hydroxyl radical formation by daunorubicin and Adriamycin was not mediated by QAO in MCF-7 S9 fraction; (iii) hydroxyl radical formation by mitomycin C was stimulated in MCF-7 S9 fraction when QAO was inhibited by dicumarol; (iv) no hydroxyl radical formation was detected for 1,4AQ or mitoxantrone in MCF-7 S9 fraction. This study shows that purified rat liver QAO can mediate hydroxyl radical formation by a variety of diverse quinone antitumour agents. However, QAO did not necessarily contribute to hydroxyl radical formation by these agents in MCF-7 S9 fraction and in the case of mitomycin C, QAO played a protective role against hydroxyl radical formation.
Topics: Animals; Antineoplastic Agents; Electron Spin Resonance Spectroscopy; Free Radicals; NAD(P)H Dehydrogenase (Quinone); Quinones; Rats; Subcellular Fractions; Substrate Specificity; Tumor Cells, Cultured
PubMed: 8403076
DOI: 10.1016/0009-2797(93)90088-g -
American Journal of Clinical Oncology Aug 1993The CNS Cancer Consortium has conducted a phase III study comparing diaziquone (AZQ) with carmustine (BCNU) in the treatment of adults with primary anaplastic glial... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
An analysis of radiotherapy data from the CNS cancer consortium's randomized prospective trial comparing AZQ to BCNU in the treatment of patients with primary malignant brain tumors. The CNS cancer consortium.
The CNS Cancer Consortium has conducted a phase III study comparing diaziquone (AZQ) with carmustine (BCNU) in the treatment of adults with primary anaplastic glial brain tumors. Patients eligible for this study were 18 years of age or older at the time of biopsy, subtotal resection, or gross total resection of an anaplastic glial brain tumor. Within 3 weeks of surgery, patients received whole brain radiotherapy at 1.7 to 2 Gy per fraction to a total whole brain dose of 42-48 Gy. This was followed by a boost to the tumor bed as ascertained by computed tomography (CT), angiography, and/or magnetic resonance imaging (MRI) of 1.7 to 2 Gy per fraction to a dose of 12-19 Gy. The recommended cumulative dose to the tumor bed was therefore 55-61 Gy. At 8 weeks following radiotherapy, patients were randomized to receive either AZQ at 15 mg/day for 3 days i.v. every 4 weeks or BCNU at 200 mg i.v. every 8 weeks. Chemotherapy was continued for at least 1 year unless death occurred, treatment failure was declared, or toxicity necessitated alteration of therapy. In the 249 randomized patients, there was no difference between the AZQ- and BCNU-treated patients in age, sex distribution, race, tumor histology, type of surgical resection, or Karnofsky performance status (KPS). Age and KPS at the initiation of therapy and tumor histology were the best overall predictors of survival. The type of chemotherapy (AZQ vs BCNU) was not predictive of survival. Two-year Kaplan-Meier survival was 22% in the AZQ-treated patients and 25% in BCNU-treated patients. In an analysis of radiotherapy administered we found that, within the range of doses required for this study, there was no influence of whole brain dose, boost dose, total dose, or size of the boost field on survival. The institution providing radiotherapy (teaching hospital vs nonteaching facility) did not influence survival.
Topics: Adult; Aged; Aged, 80 and over; Astrocytoma; Aziridines; Benzoquinones; Brain Neoplasms; Carmustine; Chemotherapy, Adjuvant; Combined Modality Therapy; Dose-Response Relationship, Radiation; Female; Glioblastoma; Glioma; Humans; Male; Middle Aged; Oligodendroglioma; Radiography; Radiotherapy Dosage; Survival Analysis
PubMed: 8392285
DOI: 10.1097/00000421-199308000-00001 -
Seminars in Oncology Aug 1993Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without... (Review)
Review
Preparative regimens used prior to bone marrow transplantation (BMT) in patients with malignancies must mediate engraftment and eradicate malignant cells without producing significant extramedullary toxicities. The first agents to be tested in BMT preparative regimens, total body irradiation (TBI) and cyclophosphamide (Cy), were ineffective as single agents, but resulted in long-term disease-free survival in some leukemic patients when combined. However, Cy/TBI regimens are associated with significant acute and chronic toxicities as well as technical constraints involving the administration of radiation. Accordingly, a nonradiation-based regimen consisting of Cy and busulfan (Bu) was developed. Regimens using either a 4-day course (BuCy4) or a 2-day course (BuCy2) of Cy have been shown to have significant antileukemic effects. In general, however, BuCy regimens do not appear to result in greater antileukemic activity or lower treatment-related toxicity than Cy/TBI regimens. New preparative regimens are currently being developed to lower the incidence of disease recurrence after BMT. One such regimen consists of BuCy plus etoposide. At our institution, we are currently testing the efficacy and toxicity of regimens in which cytarabine or diaziquone are administered in combination with Bu and Cy. It is hoped that these new preparative regimens will enhance the antileukemic effects of BMT without significantly increasing treatment-related toxicity.
Topics: Antineoplastic Combined Chemotherapy Protocols; Aziridines; Benzoquinones; Bone Marrow Transplantation; Busulfan; Cyclophosphamide; Cytarabine; Drug Monitoring; Humans; Premedication; Whole-Body Irradiation
PubMed: 8342077
DOI: No ID Found -
Journal of Medicinal Chemistry Jun 1993A series of 4,5-diamino-substituted-1,2-benzoquinones were prepared from catechol and the corresponding secondary amines in high yield in a single step using copper...
A series of 4,5-diamino-substituted-1,2-benzoquinones were prepared from catechol and the corresponding secondary amines in high yield in a single step using copper complex formation to stabilize the intermediate. The cytotoxicity of the products under various conditions was evaluated using the EMT-6 mammary carcinoma cell line, and antitumor activity was tested in the L1210 murine leukemia. The 4,5-diaziridinyl-1,2-benzoquinone was a more potent cytotoxic agent than diaziquone (AZQ) and was very effective against the L1210 leukemia. The azetidine, pyrrolidine, and diethylamine derivatives were not effective antitumor agents.
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Cell Hypoxia; Drug Screening Assays, Antitumor; Hydrogen-Ion Concentration; Leukemia L1210; Mammary Neoplasms, Experimental; Mice; Mice, Inbred DBA; Tumor Cells, Cultured
PubMed: 8515418
DOI: 10.1021/jm00065a001 -
International Journal of Radiation... Jun 1993We evaluated the potentiating effects of aziridinylbenzoquinone (AZQ) and cis-platinum on the prolongation of survival by radiation therapy in a rat brain tumor model.
PURPOSE
We evaluated the potentiating effects of aziridinylbenzoquinone (AZQ) and cis-platinum on the prolongation of survival by radiation therapy in a rat brain tumor model.
METHODS AND MATERIALS
On day 10 following intracranial inoculation of the 9L gliosarcoma, Fischer 344 rats were treated with radiation therapy (Cesium-137 source irradiator) and/or chemotherapy delivered either systemically (intraperitoneal or intravenous), or intracranially directly into the tumor in a volume of 5 microliters. Increased life spans were calculated relative to the median survival time for the control (ILS-C) or to the median survival time for radiation therapy only (ILS-RT) group.
RESULTS
Median survival time for untreated rats was 22 +/- 3 days for seven experiments. Radiation therapy (16 Gy) produced a significant (p < 0.002) improvement in survival, with an average ILS-C of 75 +/- 19%. Systemic AZQ (1 or 5 intravenous injections of 0.5 mg/kg) produced ILS's of 0 and 23%, the latter being significant (p = 0.002). When added to radiation therapy, there were further improvements (ILS-RT's of 47 and 72%), but these were not significant. Intratumor AZQ (40 or 50 micrograms intracranially) produced significant ILS-C's of 30 and 33% (p = 0.01 and 0.0002, respectively). Added to radiation therapy, intracranial AZQ produced improvements (ILS-RT's of 5 and 102%), with only the latter being significantly improved (p = 0.009). Cis-platinum (3 micrograms intracranially) produced ILS-C's of 13 and 6%, neither significantly different from controls. Added to radiation therapy, cisplatinum caused improvements (ILS-RT's of 18 and 64%), with only the latter significant (p = 0.049).
CONCLUSION
These results demonstrate that AZQ delivered systemically, and AZQ and cis-platinum delivered intracranially, can produce statistically significant improvements in the survival of rats burdened with the 9L brain tumor. The agents delivered intracranially significantly potentiated the prolongation of survival obtained by radiation therapy. This preclinical evidence suggests that combining radiation therapy with these cytotoxic chemotherapeutic agents may benefit patients with high-grade malignant brain tumors.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aziridines; Benzoquinones; Brain Neoplasms; Cesium Radioisotopes; Cisplatin; Combined Modality Therapy; Disease Models, Animal; Humans; Male; Rats; Rats, Inbred F344; Survival Rate
PubMed: 8514542
DOI: 10.1016/0360-3016(93)90962-u -
Cancer Metastasis Reviews Jun 1993NAD(P)H:Quinone Oxidoreductase1 (NQO1) also known as DT-diaphorase is a flavoprotein that catalyzes the two-electron reduction of quinones, quinone imines and azo-dyes... (Review)
Review
NAD(P)H:Quinone Oxidoreductase1 (NQO1) also known as DT-diaphorase is a flavoprotein that catalyzes the two-electron reduction of quinones, quinone imines and azo-dyes and thereby protects cells against mutagenicity and carcinogenicity resulting from free radicals and toxic oxygen metabolites generated by the one-electron reductions catalyzed by cytochromes P450 and other enzymes. High levels of NQO1 gene expression have been observed in liver, lung, colon and breast tumors as compared to normal tissues of the same origin. The transcription of the NQO1 gene is activated in response to exposure to bifunctional (e.g. beta-naphthoflavone (beta-NF), 2, 3, 7, 8 tetrachorodibenzo-p-dioxin (TCDD)) and monofunctional (phenolic antioxidants/chemoprotectors e.g. 2(3)-tert-butyl-4-hydroxy-anisole (BHA)) inducers. The high level of expression of the NQO1 gene and its induction by beta-NF and BHA require the presence of an AP1 binding site contained within the human Antioxidant Response Element (hARE) and are mediated by products of proto-oncogenes, Jun and Fos. Induction of NQO1 gene expression involves transfer of a redox signal from xenobiotics to unknown 'redox protein(s)' which in turn, modify the Jun and Fos proteins for greater affinity towards the AP1 site of the NQO1 gene and activates transcription. The expression and regulation of the NQO1 gene is complex as many additional cis-elements have been identified in the promoter region and is a subject of great future interest. In addition to established tumors, NQO1 gene expression is also increased in developing tumors, indicating a role in cellular defense during tumorigenesis. It has been proposed that low molecular weight substance(s) can diffuse from tumor cells into surrounding normal cells and activate the expression of the NQO1 gene. Purification and characterization of such substance(s) may provide important information in regard to the mechanism of activation of NQO1 gene expression and the role of increased NQO1 expression in tumor development. In view of the general consensus that NQO1 is over-expressed in tumor cells and the realization that NQO1 may either activate or detoxify xenobiotics, it is important to establish the role of NQO1 in the activation, and the detoxification of xenobiotics and drugs and in the intrinsic sensitivity of tumors to bioreductive alkylating aziridinyl benzoquinones such as diaziquone (AZQ), mitomycin C (MMC), and indoloquinone EO9, as well as to the dinitrophenyl aziridine, CB1954, and the benzotriazine-di-N-oxide, SR 4233.
Topics: Animals; Antineoplastic Agents; Base Sequence; Breast; Breast Neoplasms; Colon; Colonic Neoplasms; Enzyme Induction; Female; Gene Expression; Humans; Liver; Liver Neoplasms; Lung; Lung Neoplasms; Molecular Sequence Data; NAD(P)H Dehydrogenase (Quinone); Neoplasms; Neoplasms, Experimental; Oligodeoxyribonucleotides; Quinones; Reference Values; Xenobiotics
PubMed: 8375015
DOI: 10.1007/BF00689804 -
Biochemistry Apr 1993The nucleotide sequence preferences for the formation of interstrand cross-links induced in DNA by 2,5-diaziridinyl-1,4-benzoquinone (DZQ) and...
The nucleotide sequence preferences for the formation of interstrand cross-links induced in DNA by 2,5-diaziridinyl-1,4-benzoquinone (DZQ) and 3,6-dimethyl-2,5-diaziridinyl-1,4-benzoquinone (MeDZQ) were studied using synthetic duplex oligonucleotides and denaturing polyacrylamide gel electrophoresis (PAGE). Reaction of these bifunctional alkylating agents with a DNA duplex containing several potential cross-linking sites resulted in the formation of cross-linked DNAs with different electrophoretic mobilities. Analysis of the principal cross-linked products by piperidine fragmentation revealed that the preferential site of cross-linking was altered from a 5'-GNC to a 5'-GC sequence upon reduction of DZQ to the hydroquinone form by the enzyme DT-diaphorase. In contrast, the reduced form of MeDZQ was found to preferentially cross-link at 5'-GNC sites within the same sequence. These preferences were confirmed in duplex oligonucleotides containing single potential cross-linking sites. Additional minor cross-linked products were characterized and revealed that DZQ and MeDZQ are both capable of cross-linking across four base pairs in a 5'-GNNC sequence.
Topics: Alkylation; Aziridines; Base Sequence; Benzoquinones; Cross-Linking Reagents; DNA; Guanine; Molecular Sequence Data; NAD(P)H Dehydrogenase (Quinone); Oligodeoxyribonucleotides; Oxidation-Reduction
PubMed: 8461296
DOI: 10.1021/bi00064a013