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The American Journal of Pediatric... 1990Seventy-two children with recurrent, progressive, or metastatic lymphomas and other solid tumors, exclusive of primary central nervous system (CNS) tumors, were treated... (Clinical Trial)
Clinical Trial
Seventy-two children with recurrent, progressive, or metastatic lymphomas and other solid tumors, exclusive of primary central nervous system (CNS) tumors, were treated with aziridinylbenzoquinone (AZQ, diaziquone) at 9 mg/m2/day by 30-min intravenous infusion for 5 days every 3 weeks. Fifty-four patients were evaluable for response. Three partial responses occurred, two in patients with recurrent Hodgkin's disease and one in a patient with intraocular retinoblastoma. Sufficient numbers of patients with osteosarcoma, neuroblastoma, and Wilms' tumor were evaluable to demonstrate inactivity of this dosing regimen in these tumor types. Numbers of evaluable patients for other tumor types were insufficient to conclusively demonstrate inactivity. Myelosuppression, which was profound and prolonged, was observed. As administered in this study, AZQ has marginal activity and severe myelotoxicity in children with solid tumors.
Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Bone Marrow Diseases; Child; Child, Preschool; Drug Evaluation; Humans; Infant; Lymphoma; Neoplasm Recurrence, Local; Neoplasms
PubMed: 2240475
DOI: 10.1097/00043426-199023000-00009 -
Cancer Chemotherapy and Pharmacology 1987Diaziquone (AZQ) is a lipophilic alkylating agent which crosses the blood-brain barrier and has marked antitumor activity in a broad spectrum of murine tumor systems....
Diaziquone (AZQ) is a lipophilic alkylating agent which crosses the blood-brain barrier and has marked antitumor activity in a broad spectrum of murine tumor systems. Myelosuppression has been the dose-limiting toxicity in phase I trials. In this study 36 patients with head and neck cancer received diaziquone. Thirty-one of these patients (28 male, 3 female) were evaluable for efficacy. The initial starting dose was 7 mg/m2/day X 5 days i.v. repeated every 28 days. Because of the severe myelosuppression encountered in the first four patients, the starting dose was decreased by 20% to 5.5 mg/m2/day X 5 days repeated every 28 days. The majority of patients were considered to be good-risk patients as evidenced by performance status (80% 0-1 Zubrod) and prior therapy. Even with this dosage reduction, myelosuppression (especially thrombocytopenia) was again the dose-limiting toxicity with 25% of patients experiencing granulocyte and platelet nadirs below 1000/mm3 and 50,000/mm3 respectively. Thirty-five percent of patients required a subsequent dosage reduction of 20% prior to receiving a second course of therapy. There was one complete (CR), four partial (PR) and three minor (MR) responses. All but the CR were of relatively short duration (mean of 30 days). The patient with a CR has remained disease-free for nearly 3 years. In this group of patients the activity of diaziquone as a single agent at this dose and schedule (CR + PR + MR = 26%; CR + PR = 16%) is less than that of methotrexate, bleomycin, and cis-platinum but is encouraging. Further trials utilizing combinations are warranted.
Topics: Adult; Aged; Aziridines; Azirines; Benzoquinones; Carcinoma, Squamous Cell; Drug Evaluation; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged
PubMed: 3581421
DOI: 10.1007/BF00252985 -
European Journal of Cancer & Clinical... Feb 1983Forty-two evaluable patients with malignant melanoma received AZQ 27 mg/m2 i.v. every 4 weeks. In 5 patients with poor marrow reserve this dose was reduced to 20 mg/m2....
Forty-two evaluable patients with malignant melanoma received AZQ 27 mg/m2 i.v. every 4 weeks. In 5 patients with poor marrow reserve this dose was reduced to 20 mg/m2. Doses were rapidly escalated when no significant myelosuppression was encountered in previous courses. Twenty-five patients had received no prior chemotherapy. A single partial response was obtained for 3 months. Inconsistent myelosuppression was the main toxic effect in this trial. The median WBC and platelet nadirs were 3200/mm3 (900-19,500) and 105,000/mm3 (33,000-530,000) respectively. In 2 patients leukopenia was complicated by a transient episode of infection. One-third of the patients did not experience significant myelosuppression. Non-hematologic adverse reactions were generally mild to moderate and consisted of nausea and vomiting in 26 patients and alopecia in 1. It is concluded that at this dose schedule AZQ is ineffective against malignant melanoma.
Topics: Adult; Aged; Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Blood Cell Count; Bone Marrow Diseases; Drug Administration Schedule; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Melanoma; Middle Aged; Soft Tissue Neoplasms
PubMed: 6681775
DOI: 10.1016/0277-5379(83)90430-3 -
Radiation Oncology (London, England) Aug 2023Hypothyroidism (HT) and subclinical HT after radiotherapy is frequent in nasopharyngeal carcinoma (NPC) patients, results in negative impact on patients' quality of... (Randomized Controlled Trial)
Randomized Controlled Trial
Thyroid V40 is a good predictor for subclinical hypothyroidism in patients with nasopharyngeal carcinoma after intensity modulated radiation therapy: a randomized clinical trial.
BACKGROUND
Hypothyroidism (HT) and subclinical HT after radiotherapy is frequent in nasopharyngeal carcinoma (NPC) patients, results in negative impact on patients' quality of life. The percentage of thyroid volume receiving more than 40 Gy (V40) ≤ 85% was reported to be a useful dose constraint to adopt during intensity-modulated radiation therapy (IMRT) planning. This study aims to verify whether V40 ≤ 85% can be used as an effective dose constraint in IMRT planning in a randomized clinical trial.
METHODS
This single-center 1:1 randomized clinical trial was conducted in Fujian province hospital between March 2018 and September 2022. All patients were treated with IMRT and randomized to induction chemo followed by concurrent chemo-IMRT or concurrent chemo-IMRT alone. Ninety-two clinically NPC patients were included in this study. The thyroid function tests were performed for all patients before and after radiation at regular intervals. Thyroid dose-constraint was defined as V40 ≤ 85%. The primary outcome in this study was subclinical HT.
RESULTS
Median follow up was 34 months. Significant difference in the incidence of subclinical HT between the thyroid dose-constraint group and unrestricted group was observed (P = 0.023). The risk of subclinical HT in the thyroid dose-constraint group was lower than that in the unrestricted group (P = 0.022). Univariate and multivariate cox regression analysis indicated that thyroid dose-constraint was a protective effect of subclinical HT (HR = 0.408, 95% CI 0.184-0.904; HR = 0.361, 95% CI 0.155-0.841).
CONCLUSION
V40 ≤ 85% can be used as an effective dose constraint in IMRT planning to prevent radiation-induced subclinical HT.
Topics: Humans; Nasopharyngeal Carcinoma; Quality of Life; Radiotherapy, Intensity-Modulated; Hypothyroidism; Nasopharyngeal Neoplasms
PubMed: 37626342
DOI: 10.1186/s13014-023-02329-x -
Biochimica Et Biophysica Acta Jul 1983The enzymatically generated free radical of the antitumor agent diaziquone is analyzed with the help of two analogs where either the aziridine rings (RQ14) or the...
The enzymatically generated free radical of the antitumor agent diaziquone is analyzed with the help of two analogs where either the aziridine rings (RQ14) or the carboethoxyamino groups (RQ2) were substituted by chlorine atoms. The hyperfine couplings observed in the diaziquone free radical are due to the nitrogens in the aziridine group. Unresolved coupling and hindered rotation contribute to line broadening. We find that diaziquone free radicals are more stable than RQ14 but less stable than RQ2 free radicals. The reason for this is that the carboethoxyamino groups make the aromatic ring unstable, while the aziridines contribute to its stability. The free radical observed in diaziquone is in all probability that of the parent compound and not that of an intermediate metabolite.
Topics: Antineoplastic Agents; Aziridines; Azirines; Benzoquinones; Biotransformation; Electron Spin Resonance Spectroscopy; Free Radicals; Kinetics; NADPH-Ferrihemoprotein Reductase
PubMed: 6305426
DOI: 10.1016/0304-4165(83)90007-7 -
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 -
Journal of Clinical Oncology : Official... Jan 1992Because there is a compelling need to develop new agents for intrathecal use, we investigated the safety, efficacy, and CSF pharmacokinetics of diaziquone (AZQ)... (Clinical Trial)
Clinical Trial
PURPOSE
Because there is a compelling need to develop new agents for intrathecal use, we investigated the safety, efficacy, and CSF pharmacokinetics of diaziquone (AZQ) following intrathecal administration in patients with refractory meningeal malignancies.
PATIENTS AND METHODS
Thirty-nine patients received 45 courses of intrathecal AZQ. Two schedules were studied; twice-weekly administration of a 1- or 2-mg dose and "concentration times time" (C x T) administration of 0.5 mg every 6 hours for three doses, administered once weekly.
RESULTS
Dose-limiting toxicity consisting of headache, nausea, or vomiting occurred in only three patients and only at the 2-mg, twice weekly dose. The schedules of 1 mg twice-weekly and 0.5 mg every 6 hours for three doses were well tolerated. Thirty-seven courses were assessable for response. The overall response rate was 62%. Complete responses (CRs) occurred in 14 of 37 courses (38%) and partial responses (PRs) occurred in nine of 37 courses (24%). Among patients with meningeal leukemia, CRs were observed in 11 of 26 courses (42%) and PRs in nine of 26 courses (35%). There was no difference in response rate related to dose or schedule. The pharmacokinetic behavior of intrathecally administered AZQ was characterized by biexponential disappearance from ventricular CSF, with mean half-lives of 18.2 and 78.6 minutes. The mean clearance rate was 0.37 mL/min.
CONCLUSION
Intrathecal AZQ is safe, well tolerated, and highly active against refractory meningeal malignancies.
Topics: Adolescent; Adult; Antineoplastic Agents; Aziridines; Benzoquinones; Child; Child, Preschool; Drug Administration Schedule; Drug Evaluation; Female; Humans; Injections, Spinal; Male; Meningeal Neoplasms; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 1727916
DOI: 10.1200/JCO.1992.10.1.143 -
Clinical Pharmacokinetics 2005Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS.... (Review)
Review
Intraventricular administration of chemotherapy is one approach to overcoming the limited distribution of anticancer drugs and their active metabolites into the CNS. This form of regional chemotherapy has led to effective treatment of occult and overt meningeal leukaemia in humans. In contrast, the efficacy of this therapy is extremely limited in the treatment of leptomeningeal dissemination of various solid tumours. Pharmacokinetic studies of the commonly intraventricularly applied anticancer agents in humans have demonstrated that, using low drug doses, very high drug concentrations can be achieved in the cerebrospinal fluid (CSF) and relatively high concentrations in the leptomeninges but not in the brain tissue and the plasma. Therefore, this approach is not an effective treatment for bulky disease of brain tissue, and results in minimal systemic toxicity. In comparison with intralumbar administration, lower interpatient variability of CSF drug concentrations and improved clinical efficacy were observed. 'Concentration x time' schedules, i.e. frequent small drug doses over a short period, enable long-term CSF exposure to cytotoxic drug concentrations while avoiding excessively high and potentially neurotoxic drug concentrations. The technique of ventriculolumbar cerebrospinal perfusion delivers continuously high drug concentrations throughout the CSF for several hours, but its widespread use is limited by the technical complexities of this approach. In this article, the dosages, schedules and pharmacokinetic data of routinely used intraventricular agents in humans, e.g. methotrexate, cytarabine, glucocorticoids and thiotepa, are outlined in detail. In addition, pharmacokinetic data of investigational agents for intraventricular administration (diaziquone, DTC 101, mercaptopurine, mafosfamide, etoposide, topotecan, nimustine [ACNU] and bleomycin) are presented. Better understanding of the CSF pharmacology of these drugs is an essential prerequisite for safe, effective administration of these drugs. Investigational efforts are underway to verify the feasibility and efficacy of different dosages, schedules and combination therapies of these new intra-CSF agents. Current and future clinical research should also focus on methods allowing the delivery of tumoricidal drug concentrations for extended periods into the CSF and the brain tissue while minimising neurotoxicity and systemic toxicity (e.g. liposomal drug preparations, monoclonal antibodies, immunotoxins and gene therapy).
Topics: Adolescent; Adult; Animals; Antineoplastic Agents; Cerebrospinal Fluid; Child; Drug Administration Schedule; Humans; Infusion Pumps, Implantable; Injections, Intraventricular; Injections, Spinal; Meningeal Neoplasms; Metabolic Clearance Rate
PubMed: 15634030
DOI: 10.2165/00003088-200544010-00001 -
Biochemical Pharmacology Apr 1992
Review
Topics: Animals; Antineoplastic Agents; Aziridines; Benzoquinones; Dihydrolipoamide Dehydrogenase; Drug Design; Enzyme Induction; Gene Expression Regulation, Enzymologic; Humans; Indolequinones; Indoles; Mitomycin; Neoplasms; Precancerous Conditions; Tirapazamine; Triazines
PubMed: 1575764
DOI: 10.1016/0006-2952(92)90694-e -
Free Radical Biology & Medicine 1991One-electron reduction of diaziquone (AZQ) by purified rat liver NADPH cytochrome c reductase was associated with formation of AZQ semiquinone, superoxide anions,...
Free radical formation and DNA strand breakage during metabolism of diaziquone by NAD(P)H quinone-acceptor oxidoreductase (DT-diaphorase) and NADPH cytochrome c reductase.
One-electron reduction of diaziquone (AZQ) by purified rat liver NADPH cytochrome c reductase was associated with formation of AZQ semiquinone, superoxide anions, hydrogen peroxide, and hydroxyl radicals as indicated by ESR spin-trapping studies. Reactive oxygen formation correlated with AZQ-dependent production of single and double PM2 plasmid DNA strand breaks mediated by this system as detected by gel electrophoresis. Direct two-electron reduction of AZQ by purified rat liver NAD(P)H (quinone acceptor) oxidoreductase (QAO) was also associated with formation of AZQ semiquinone, superoxide anions, hydrogen peroxide, and hydroxyl radicals as detected by ESR spin trapping. Furthermore, PM2 plasmid DNA strand breaks were detected in the presence of this system. Plasmid DNA strand breakage was inhibited by dicumarol (49 +/- 5%), catalase (57 +/- 2.3%), SOD (42.2 +/- 3.6%) and ethanol (41.1 +/- 3.9%) showing QAO and reactive oxygen formation was involved in the PM2 plasmid DNA strand breaks observed. These results show that both one- and two-electron enzymatic reduction of AZQ give rise to formation of reactive oxygen species and DNA strand breaks. Autoxidation of the AZQ semiquinone and hydroquinone in the presence of molecular oxygen appears to be responsible for these processes. QAO appears to be involved in the metabolic activation of AZQ to free radical species. The cellular levels and distribution of this enzyme may play an important role in the response of tumor and normal cells to this antitumor agent.
Topics: Animals; Aziridines; Benzoquinones; DNA Damage; Electron Spin Resonance Spectroscopy; Free Radicals; Liver; NAD(P)H Dehydrogenase (Quinone); NADH Dehydrogenase; Oxidation-Reduction; Plasmids; Rats
PubMed: 1663902
DOI: 10.1016/0891-5849(91)90141-o