Disease relevance of nitrosourea

• Delayed pulmonary fibrosis after nitrosourea therapy [1].
• Renal-failure anemia and nitrosourea therapy [2].
• In addition, no excess of acute nonlymphocytic leukemia was seen in 44,370 patients treated for gastrointestinal cancer in Connecticut during the period 1935 to 1974, before the advent of nitrosourea chemotherapy [3].
• Nitrosoureas form O6-alkylguanine-DNA adducts that are converted to G to A transitions, the mutation found in the activated ras oncogenes of nitrosourea-induced mouse lymphomas and rat mammary tumors [4].
• Serologic analysis of nitrosourea-induced rat gliomas [5].

Psychiatry related information on nitrosourea

• Dementia following treatment of brain tumors with radiotherapy administered alone or in combination with nitrosourea-based chemotherapy: a clinical and pathological study [6].

High impact information on nitrosourea

• We have pursued our findings of glutathione reductase (GSSG-R) deficiency and disturbed glutathione in cancer patients treated with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), by investigating how thiol metabolism, cell proliferation, and the nitrosourea interact in human K562 leukemia [7].
• By destroying GSSG-R and delaying the upregulation of thiol synthesis while escalating GSH utilization and requirements, the nitrosourea created a striking and previously unrecognized window of vulnerability for GSH-dependent processes [7].
• Enhancement of nitrosourea activity in medulloblastoma and glioblastoma multiforme [8].
• Interim report of phase II study of new nitrosourea S 10036 in disseminated malignant melanoma [9].
• Significance of DNA cross-links on 1-(4-amino-2-methylpyrimidin-5-yl)methyl-3-(2-chloroethyl)-3- nitrosourea (ACNU)-induced cytotoxicity against ACNU-sensitive and -resistant lines of 9L rat glioma cells [10].

Chemical compound and disease context of nitrosourea

• Eight patients with stage III aggressive multiple myeloma, refractory to current chemotherapy in six cases, were treated by high-dose chemotherapy (nitrosourea, etoposide, and melphalan) (HDC) and total body irradiation (TBI), followed by autografting with blood stem cells [11].
• CONCLUSION: These results indicate that O(6)-BG plus BCNU at the dose schedule used in this trial is unsuccessful in producing tumor regression in patients with nitrosourea-resistant malignant glioma, although stable disease was seen in five patients for 6, 12, 12, 12, and 18 weeks [12].
• Sensitization of nitrosourea-resistant Mer+ human tumor cells to N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea by mild (41 degrees C) hyperthermia [13].
• Cancer cachexia was induced in mice with colon 26 adenocarcinoma, which is a small and slow-growing tumor characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12ClN3O4S) [14].
• Chlorozotocin, 2-(3-(2-chloroethyl)-3-nitrosoureido)-D-glucopyranose, is a newly synthesized, water-soluble nitrosourea antitumor agent that is active against L1210 leukemia in mice [15].

Biological context of nitrosourea

• The objective of this study was to determine if HeLa cells irreversibly arrested in G2 phase of the cell cycle by a brief exposure to a nitrosourea compound were deficient in certain proteins when compared with G2-synchronized cells [16].
• These studies show that nitrosourea resistance in myeloid leukemic cells can be abrogated by inactivation of the DNA repair protein O6-alkylguanine-DNA alkyltransferase [17].
• These data suggest that the lethal damage of nitrosourea alkylation in human bone marrow is principally expressed in transcriptionally active regions of chromatin [18].
• Long-term protection of hematopoiesis against the cytotoxic effects of multiple doses of nitrosourea by retrovirus-mediated expression of human O6-alkylguanine-DNA-alkyltransferase [19].
• In contrast, resting lymphocytes do not rapidly synthesize new alkyltransferase molecules after nitrosourea exposure and appear susceptible to DNA damage caused by persistent O6-alkylguanine adducts [20].

Anatomical context of nitrosourea

• No enhancement of nitrosourea-induced leukemogenesis was apparent, although a slight promoting effect was demonstrated for renal and thyroid tumorigenesis [21].
• This finding may be responsible for the cumulative toxicity to the human hematopoietic system that frequently has been observed after repeated administration of nitrosourea compounds [22].
• G-CFUc compartments of bone marrow and peripheral blood continued to be reduced in size at the time of recovery of the peripheral blood granulocyte count from nitrosourea-induced toxicity [22].
• These cells, derived from a nitrosourea-induced mouse brain neoplasm, have some of the morphological characteristics of smooth muscle and have been shown to express the vascular smooth muscle isoform of alpha-actin [23].
• This study confirms that the cell content in this repair DNA protein is certainly one of the important factors implicated in the variability of response to 2-chloroethyl nitrosourea treatment observed in a number of established malignant cell lines [24].

Associations of nitrosourea with other chemical compounds

• Selective activation of human heat shock gene transcription by nitrosourea antitumor drugs mediated by isocyanate-induced damage and activation of heat shock transcription factor [25].
• O6-benzylguanine (O6-BG), a potent inhibitor of the DNA repair protein, O6-alkylguanine-DNA alkyltransferase (AGT), has been shown to reduce nitrosourea resistance and, thus, enhance the efficacy of systemic BCNU therapy in a variety of tumor models [26].
• While further studies are needed to document that biochemical modulation can be achieved in the target tumor in humans, this study supports the development of clinical trials using streptozotocin as a biochemical modulator of nitrosourea resistance in human malignancies [27].
• The effects of the nitrosourea cystemustine were investigated in skeletal muscles from both healthy and colon 26 adenocarcinoma-bearing mice, an appropriate model for testing the impact of cytostatic agents [28].
• To further define this protective role conferred by the glucose moiety in bone marrow cells, we have replaced the nitrosourea cytotoxic group with another class of alkylating agent, a bifunctional nitrogen mustard [29].

Gene context of nitrosourea

• Transient induction of the MRP/GS-X pump and gamma-glutamylcysteine synthetase by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3- nitrosourea in human glioma cells [30].
• Msh2 deficiency reduced the apoptotic response to each agent, but only led to increased crypt survival after NMNU treatment [31].
• These findings highlight the importance of MGMT methylation as a specific predictive factor for responsiveness to nitrosourea chemotherapy [32].
• These results indicate that the MDR1-MGMT bicistronic retrovirus vectors would be useful to protect normal hematopoietic cells from nitrosourea-induced mutagenesis, and drug-selectable bicistronic constructs would have great advantage over non-selectable vectors [33].
• With the exception of the monofunctional nitrosourea, streptozotocin, both recA and uvrA gene products contribute to the repair of DNA damage caused by the alkylating agents tested [34].

Analytical, diagnostic and therapeutic context of nitrosourea

• PURPOSE: A phase II study was conducted in patients with high-grade gliomas that recurred after surgery plus radiotherapy and a first-line nitrosourea-based regimen [35].
• O6-benzlguanine (O6-bG) potentiates nitrosourea cytotoxicity of human tumor xenografts in nude mice by inactivating O6-alkylguanine-DNA alkyltransferase (AGT) [36].
• Two major modified base peaks were observed from the nitrosourea treated sample which have been subsequently identified by high-pressure liquid chromatography comparison of synthesized standards and by electron impact gas chromatography/mass spectrometric analysis to be 7-hydroxyethylguanine and 7-chloroethylguanine [37].
• Fourteen patients were treated adjuvantly with radiotherapy and nitrosourea-based chemotherapy; six were treated at recurrence following initial gross total resection with reoperation (subtotal resection in all), radiotherapy, and nitrosourea-based chemotherapy [38].
• Immunity to transplantable nitrosourea-induced neurogenic tumors. III. Systemic adoptive transfer of immunity [39].

References