Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the antitumor effects of chloroethylnitrosoureas have been shown to be due primarily to DNA-DNA cross-linking by the alkylating moieties of these agents, the basis of the often accompanying bone marrow toxicity has been more controversial. We report on the relative bone marrow toxicity of four model nitrosoureas with different alkylating and carbamoylating activities: 1,3-bis(2-chloroethyl)-1-nitrosourea; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea; chlorozotozin, (2-[3-(2-chloroethyl)-3 -nitrosoureido]-2-deoxy-D-glucopyranose); and -3-(beta-D-glucopyranosyl)-1-nitrosourea. Inhibitions of DNA, RNA, and protein synthesis in murine bone marrow cells and of colony growth of myeloid precursor cells (granulocyte-macrophage colony-forming units) were used as in vitro end points of myelotoxicity. Further, we determined the antiglioma activity of the four nitrosoureas on two human gliomas in a clonogenic tumor cell assay and studied the effect of the non-nitrosourea carbamoylators potassium cyanate, chloroethyl isocyanate, cyclohexyl isocyanate, ethyl isocyanate, and ethyl isothiocyanate on granulocyte-macrophage colony-forming units. The results show that, at equivalent drug exposures, clonogenic glioma cell kill was significant and comparative for 1,3-bis(2-chloroethyl)-1-nitrosourea, 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea, and chlorozotocin; 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea showed little activity. In contrast, granulocyte-macrophage colony-forming unit toxicity was low with chlorozotocin and 1-(2-chloroethyl)-3-(beta-D-glucopyranosyl)-1-nitrosourea and very high with 1,3-bis(2-chloroethyl)-1-nitrosourea and 1,3-bis(trans-4-hydroxycyclohexyl)-1-nitrosourea. Of the isocyanates, bone marrow toxicity was highest with chloroethyl isocyanate and cyclohexyl isocyanate, intermediate with ethyl isocyanate, and lowest with KOCN and ethyl isothiocyanate. Our results indicate that (a) bifunctional alkylation is essential for antiglioma activity of nitrosoureas and (b) myelosuppression is at least partly linked with carbamoylation but that structural entities in the carbamoylating isocyanate rather than a quantitative degree of carbamoylation determine the degree of potential myelotoxicity.
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PMID:Chemical structure of carbamoylating groups and their relationship to bone marrow toxicity and antiglioma activity of bifunctionally alkylating and carbamoylating nitrosoureas. 241 98

Thirty-eight patients with primary recurrent anaplastic gliomas and glioblastomas, were treated with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and the polyamine inhibitor alpha-difluoromethylornithine (DFMO). There were 5 brain stem, 1 cerebellar, and 32 supratentorial glioma tumors. All had been treated with surgery (except in the case of 4 brain stem tumors for which biopsies were not obtained) and radiotherapy. Eight patients had received prior chemotherapy. Of the 21 patients with evaluable supratentorial anaplastic gliomas, 2 (9.5%) had a partial response and 10 (47.6%) had stable disease. The median time to tumor progression for the anaplastic gliomas has not been attained yet. However, median survival for these 12 patients was 119 weeks measured from the initiation of chemotherapy. Median survival for the entire anaplastic glioma group of 21 was 56 weeks. Minimal activity was seen against glioblastoma multiforme. The median time to tumor progression was 8 weeks with median survival of 21 weeks. Of the 5 patients with brain stem tumors, 3 are alive with stable disease at 77, 93, and 220 weeks. The combination was well tolerated with dose-limiting toxicity being myelosuppression and hearing loss. Further trials are warranted to compare the combination of BCNU and DFMO against BCNU alone in a prospective randomized trial.
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PMID:Treatment of recurrent gliomas with 1,3-bis(2-chloroethyl)-1-nitrosourea and alpha-difluoromethylornithine. 254 93

Autologous bone marrow transplantation allows the use of high dose chemotherapy by obviating dose limiting myelosuppression. The pharmacology of high dose chemotherapy has been inadequately explored, yet this information is critical to determine the timing of marrow infusion and assure that engraftment is not compromised. We have used the Salmonella mutagenesis test (SMT) and colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay to evaluate the optimal time for marrow infusion after therapy with high dose combinations of alkylating agents (Solid Tumor Autologous Marrow Support Program) in seven patients. The SMT is sensitive, rapidly performed, and has been used to detect mutagenic activity in urine following administration of cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea. In parallel, determination of colony forming ability of the patients own bone marrow (colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay), when cocultured with autologous serum obtained before and after treatment, provided an assay for circulating marrow toxic drugs or metabolites. The onset of mutagenic activity in the SMT and the in vitro appearance of myelotoxicity by autologous serum in the colony forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte assay were concurrent, and these activities returned to base line at the time of marrow infusion (72 h posttreatment). One patient of the seven was excreting mutagens (TA100 strain only) at the time of marrow reinfusion; he developed hepatic venoocclusive disease, and delayed engraftment. These observations suggest that as high dose regimens evolve the SMT may serve as a rapid, sensitive indicator of the circulation and excretion of toxic compounds, and thereby assist in predicting the optimum time of bone marrow reinfusion.
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PMID:Prediction of the optimal timing of bone marrow reinfusion after high dose chemotherapy. 352 14

The effects of dose and schedule of administration of either 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) or 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (HECNU) were compared in terms of induction of DNA damage in the bone marrow of male C6B3F1 mice or in the inhibition of two stem cell lines contained therein. At equimolar doses HECNU induced a 3- to 40-fold deeper nadir of proliferation of both stem cell lines compared to BCNU, but subsequently a 2- to 30-fold quicker recovery of these lines was observed. An enhancement of myelotoxicity was only found following injections with intervals of 1 week. Myelosuppression was almost twice as great, when six instead of three weekly injections of 50 mumol/kg were given. When, however, sufficient time was allowed for recovery, doubling the number of significantly larger doses of drug was tolerated at the level of the bone marrow stem cell. The maximum inhibition of pluripotent- and granulocyte-committed stem cells following HECNU was paralleled by higher amounts of DNA-DNA interstrand crosslinks in the entire bone marrow compared to BCNU. During the initial stages, the degree of myelosuppression did, to some extent, parallel the number of DNA-DNA interstrand crosslinks induced in the bone marrow as a whole, but this relation was lost after the initial period.
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PMID:Relationship between DNA damage and the inhibition of stem cells in murine bone marrow after single and repeated administration of BCNU and HECNU. 407 17

This study compares the level of DNA-DNA interstrand crosslinking in murine bone marrow with the decrease in mean number of blood progenitor cells in mice treated with chloroethylnitrosoureas. Male C57BL6 X C3HF1 mice were treated with single IP injections of 1-(2-chloroethyl)-1-nitroso-3-(methylene-carboxamido)-urea (acetamido-CNU), 1,2-bis(2-chloroethyl)-1-nitrosourea (BCNU), 2-[3-(2-chloroethyl)3-nitrosoureido]-beta-D-glucopyranose (chlorozotocin), or 1-(2-hydroxyethyl)-3-(2-chloroethyl)-3-nitrosourea (HECNU). After 16 h three aliquots of pooled bone marrow were assayed for DNA damage in the form of DNA-DNA interstrand crosslinks and myelosuppression in terms of the depletion of granulocyte-committed (CFU-C) and pluripotent (CFU-S) stem cell activity. Both acetamido-CNU and HECNU produced a dose-dependent increase in DNA-DNA interstrand crosslinking, which was paralleled by a marked inhibition of both types of progenitor cells. BCNU and chlorozotocin, however, were much less effective at crosslinking DNA, and were much less myelosuppressive in terms of CFU-C and CFU-S activity. These data suggest a correlation between the degree of myelosuppression at the level of the stem cell and the extent of DNA damage in murine bone marrow. The levels of haematosuppression did not parallel the acute single-dose toxicity in mice but rather reflected the relative antileukaemic activity of these agents. However, the degree of recovery of the stem cell compartments may be more relevant to the clinically important long-term toxicity after single and repeated doses.
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PMID:The level of DNA interstrand crosslinking in bone marrow parallels the extent of myelosuppression in mice treated with four chloroethylnitrosoureas. 623 30

We have used intra-arterial (i.a.) 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) either alone or as part of adjuvant chemotherapy in patients with malignant brain tumors over a 3 year period (1979-1982). The i.a. BCNU technique was used 111 times to infuse 134 arteries in 37 patients. These patients, 28 cases with glial tumor and 9 cases with brain metastasis, received i.a. BCNU in combination with Vincristine and Procarbazine every 6 weeks. Complications encountered were transient and included: periorbital erythralgia or occipital-nuchal pain in 23 (62%), mild confusion and disorientation in 14 (38%), and ipsilateral conjunctival edema in 10 (27%). Reversible myelosuppression was not found. Our findings suggest that BCNU (100 mg/M2) may be given by i.a. infusion in combination chemotherapy without persistent severe untoward effects with a cumulative dose of 700 mg/M2.
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PMID:Complications associated with intra-arterial BCNU administered in combination with vincristine and procarbazine for the treatment of malignant brain tumors. 648 25

Severe and delayed myelosuppression is a major side effect encountered with the clinical use of nitrosourea-type chemotherapeutic drugs. The DNA repair protein O6-methylguanine DNA methyltransferase (MGMT) has been shown to repair nitrosourea-induced DNA damage. We therefore investigated the effect of expressing MGMT in hematopoietic cells (via retrovirus-mediated gene transfer) on nitrosourea-induced toxicity. A retroviral vector (N2/ZipPGK-MGMT) expressing the human MGMT cDNA from the phosphoglycerate kinase promoter was constructed. Infection of murine bone marrow with the N2/ZipPGK-MGMT retrovirus significantly increased the survival of murine bone marrow-committed progenitor cells following in vitro exposure to N-N'-bis(2-chloroethyl)-N-nitrosourea (BCNU, carmustine). MGMT gene transfer also protected murine hematopoietic cells in vivo in a murine model of BCNU-induced myelosuppression. The infusion of 4-6 x 10(6) N2/ZipPGK-MGMT-transduced bone marrow cells into mice every 2 weeks significantly increased peripheral leukocyte counts, platelet counts, and hematocrits compared to infusions of mock-infected bone marrow cells. In addition, bone marrow-committed progenitor cells from some recipient animals demonstrated increased resistance to BCNU in vitro when analyzed 2.5 months after initial treatment. The integration of the N2/ZipPGK-MGMT provirus in the spleen DNA from these animals correlated with committed progenitor cell resistance to BCNU. These data suggest that MGMT expression in hematopoietic progenitor and precursor cells protects against nitrosourea-induced toxicity and that gene transfer may prove useful in attempts to reduce nitrosourea-induced myelosuppression in the clinical setting.
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PMID:Retrovirus-mediated expression of a DNA repair protein in bone marrow protects hematopoietic cells from nitrosourea-induced toxicity in vitro and in vivo. 778 Sep 76

The effects of a combination of simvastatin, a cholesterol-lowering agent, and carmustine (BCNU; N,N'-bis(2-chloroethyl)-N-nitrosourea) on experimental C6 glioma were studied in vitro and in vivo. In vitro simvastatin and BCNU alone inhibited cell proliferation in a dose-dependent fashion. A subliminal concentration of simvastatin (0.1 microM) markedly and synergistically increased the BCNU toxicity to C6 glioma cells. The cytofluorimetric analysis of DNA from simvastatin-treated C6 glioma cells showed, besides the already described arrest in G1, an arrest/retardation in G2-M. Mitotic index from C6 cells incubated with simvastatin (10 microM) decreased by about 90%, indicating a specific C6 arrest/retardation in G2. The drug effects could be completely reversed by simvastatin withdrawal or mevalonate addition to the cultured cells. The combination of simvastatin and BCNU resulted predominantly from the profound retardation of cells in the G2-M compartment of the cell cycle. In vivo simvastatin (administered daily mixed with food) and BCNU (single i.p. injection), when given separately, caused a dose-dependent inhibition of labeling index in C6 glioma homografts (ID50, 61 mg/kg/day and 8.7 mg/kg, respectively). The combination of the lowest doses tested (simvastatin, 25 mg/kg/day and BCNU 0.3 mg/kg) resulted in a significant growth delay (compared to either drug alone) in C6 glioma (P < 0.05). There was no significant increase in toxicity as assessed by myelosuppression (WBC counts and bone marrow labeling index) and body weight. The results provide in vivo support for the combined use of simvastatin, a cholesterol-lowering agent, and BCNU in brain tumor treatment.
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PMID:In vivo enhanced antitumor activity of carmustine [N,N'-bis(2-chloroethyl)-N-nitrosourea] by simvastatin. 783 30

The goal of this study was to determine the antitumor activity and toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus recombinant interferon-alpha (IFN-alpha) in patients with recurrent glioma. As single agents, both BCNU and IFN-alpha can cause tumor regression in patients with recurrent glioma. In vitro studies suggest synergy between the two agents. Thirty-five patients in whom computerized tomography (CT) or magnetic resonance (MR) evidence was obtained of progressive astrocytoma, oligoastrocytoma, or oligodendroglioma received recombinant IFN-alpha 2a (12 x 10(6) U/m2 intramuscularly) on Days 1 through 3 and BCNU (150 mg/m2 intravenously) on Day 3 of each 6-week cycle. All patients had tumor progression despite radiation therapy and had received no prior chemotherapy. Response was assessed by CT or MR evidence and by neurological examination while the patients were on a regimen of stable or decreasing doses of corticosteroids. All patients could be evaluated for response and toxicity. Twenty-nine percent of the patients demonstrated objective tumor regression; 37% remained stable for more than 6 months and 25% were stable for less than 6 months. The median duration of response to IFN-alpha and BCNU was 9.9 months and the median survival for all patients was 13.3 months. Toxicity consisted primarily of moderate myelosuppression, venous irritation, vomiting, flulike symptoms, and transient reversible exacerbation of underlying neurological symptoms. The use of BCNU plus IFN-alpha is a safe, active regimen in the treatment of patients with recurrent glioma who have failed to respond to prior radiation therapy. The contribution of IFN to the antitumor activity observed in this study compared with that previously described with BCNU alone cannot be assessed from this trial.
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PMID:Phase II evaluation of recombinant interferon alpha and BCNU in recurrent glioma. 786 Dec 21

The chloroethylnitrosoureas, such as 1,3-bis(2-chloroethyl)-1-nitrosourea, are alkylating agents which are thought to exert antitumor activity by initiating lethal DNA interstrand cross-links. Although nitrosoureas are among the most active agents against childhood and adult gliomas, the utility of this class of agents has been limited by severe and cumulative myelosuppression, which can be fatal. Nitrosourea-induced myelosuppression in humans is delayed and may continue after withdrawal of the agent. We have developed a murine model which mimics the delayed and cumulative myelosuppression seen in humans receiving nitrosoureas. In this model, we demonstrate that interleukin-11, a stromal-derived hematopoietic growth factor with pleiotropic effects in a number of preclinical ablation models, markedly diminishes nitrosourea-induced pancytopenia and leads to a significant reduction in chemotherapy-related mortality. These data suggest that interleukin-11 could allow significant dose intensification in the treatment of tumors which are nitrosourea sensitive.
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PMID:Increased survival and multilineage hematopoietic protection from delayed and severe myelosuppressive effects of a nitrosourea with recombinant interleukin-11. 806 61


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