Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Literature on secondary tumours developing after cancer chemotherapy with nitrosoureas is reviewed. Many case studies show that combination treatments including BCNU and CCNU give rise predominantly to acute leukaemia within an average latent period of about 40 months. However, because other, potentially carcinogenic alkylating agents may be administered during treatment, no direct causal association with nitrosoureas can be made on the basis of these studies. A large case-control study by Boice et al. (1983), however, provides strong evidence of a causal relationship between the induction of acute nonlymphocytic leukaemia (ANLL) and treatment with methyl-CCNU. Among 2067 patients treated with methyl-CCNU and 5-fluorouracil as adjuvant chemotherapy after surgery for gastrointestinal cancers, nine cases of ANLL were observed, whereas 0.71 were expected; the relative risk was 15.9. The results are discussed and are interpreted as providing evidence for the carcinogenicity of methyl-CCNU to humans. They are therefore consistent with other epidemiological data on the carcinogenicity of N-nitroso compounds to man.
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PMID:Carcinogenicity of nitrosoureas in humans. 358 92

The antitumor effects of GANU have been examined in a panel of mouse tumors for which data appear to be lacking in the literature. GANU has significant activity against P388 leukemia and TLX5 lymphoma, and also against the solid tumors B16 melanoma and Lewis lung carcinoma; pulmonary metastases of this tumor are particularly sensitive to the effects of GANU. The effects of GANU on TLX5 lymphoma and Lewis lung carcinoma are less pronounced than those of BCNU and CCNU, as already reported for L1210 leukemia. In contrast with other results obtained with this tumor, chlorozotocin has a less pronounced effect than GANU, and virtually none in lung metastases of Lewis lung carcinoma.
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PMID:Antitumor effects of GANU and other nitrosourea derivatives against transplantable leukemias and solid tumors in mice. 622 44

ACNU, GANU and MCNU, water-soluble nitrosoureas, have been evaluated in terms of influence of treatment schedule on antitumor activity in mice bearing L1210 leukemia. The results obtained were as follows: 1) ACNU produced a significant increase in life span and long-term survivors by administration on day 1 only, once every 8 days for 2 doses or once every 4 days for 3 doses, and the compound was most effective when given on day 1 only. 2) GANU produced a significant increase in life span and long-term survivors by same administration schedules as ACNU, and the compound was most effective when given every 8 days for 2 doses. 3) MCNU produced a significant increase in life span and long-term survivors by each administration including daily treatment, and the compound was most effective when given every 4 days for 3 doses. 4) ACNU and MCNU displayed the same level of activity as CCNU when the drugs were given on day 1 only. Daily treatment with MCNU was as effective as daily treatment with CCNU. Our results suggest that ACNU, GANU and MCNU should be administered by intermittent schedule as lipid-soluble nitrosoureas such as BCNU, CCNU and MeCCNU.
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PMID:[Comparative effect of administration schedules on the antitumor activities of 3 water-soluble nitrosoureas, ACNU, GANU and MCNU against L1210 leukemia]. 622 85

The uptake of radiolabeled CLZ and CCNU by L1210 leukemia and murine bone marrow cells was investigated to determine whether the preferential ratio of alkylation of L1210 DNA to murine bone marrow DNA of 1.3 by 0.1 mM CLZ, as against a ratio of 0.6 by equimolar CCNU, is secondary to differences in uptake. The concentration of intact CLZ was determined in the medium and the intracellular water space. The cell: medium ratio (intracellular concentration/medium concentration) of CLZ in bone marrow cells was greater than that seen for L1210 cells. However, the intracellular CLZ concentration generally remained constant in both cell types at 37 degrees C, between 7.0 and 10.0 pmole/microliters. The L1210: murine bone marrow cell ratio of intracellular CLZ concentrations was approximately 1.0 from 10 to 60 min. The intracellular CCNU concentration during the uptake of 0.1 mM (chloroethyl-U-14C) CCNU at 37 degrees C was constant at 85 pmol/microliters from 10 to 60 min in L1210 cells, but slowly decreased from 66 pmole/microliters at 20 min to 43 pmole/microliters at 60 min in bone marrow cells. The L1210: murine bone marrow cell ratio of intracellular CCNU concentrations ranged from 1.45 to 1.98 from 20 to 60 min. Thus, it appears that the preferential ratio of alkylation of L1210 DNA to murine bone marrow DNA by CLZ compared with equimolar CCNU cannot be explained by differences in uptake of the two agents by the two cell types. The uptake of 0.1 mM CLZ at 37 degrees C by L1210 cells in McCoy's 5A medium containing 300 mg% glucose was not affected by the addition of 5 mM cold drug, nor was it affected by the absence of glucose in the medium, with or without cold drug. This suggests that CLZ uptake into L1210 cells is via passive diffusion and that CLZ does not enter these cells via the glucose transport mechanism.
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PMID:Comparison of the transport of chlorozotocin and CCNU in L1210 leukemia and murine bone marrow cells in vitro. 622 21

Experimental studies with orally administered MCNU, a water-soluble nitrosourea, yielded the following results. MCNU produced a significant increase in life span, and 60-day survivors were observed by various schedules in L1210 leukemia. The therapeutic ratios of MCNU were almost similar to those of CCNU. With Lewis lung carcinoma and Ehrlich ascites carcinoma implanted into the stomach wall, its antitumor activity by oral administration was slightly more effective than by intravenous route. In Beagle dogs, hematologic toxicity and gastrointestinal toxicity (vomiting, diarrhea) were noted by oral administration, similar to intravenous administration, but its toxicity was mild. The maximum blood level of MCNU was noted at 30 minutes after oral administration in Beagle dogs. The half life (23.7 min) by oral administration was similar to that by intravenous route. From these results, the oral administration of MCNU deserves the consideration as a form of treatment now given other MCNU routes.
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PMID:[Experimental studies on oral administration of nitrosourea anti-tumor agent, MCNU]. 623 61

Three protocols have been evaluated by the Cancer and Leukemia Group B (CALGB) for the treatment of small cell anaplastic cancer of the lung between 1972 to 1980. The first protocol (CALBG 7283) was a randomized comparison between 4 arms: high dose cyclophosphamide alone, cyclophosphamide plus methotrexate, cyclophosphamide plus methotrexate plus vincristine, and cyclophosphamide plus high-dose methotrexate plus vincristine. Response rate and survival were not significantly different among the 4 arms. Effectiveness of prophylactic brain radiotherapy and usefulness of maintenance chemotherapy were demonstrated. The next protocols (CALGB 7781 and 7782) compared two adriamycin containing regimens: MACC (methotrexate, adriamycin, cyclophosphamide, CCNU) versus CCV/AV (cyclophosphamide, CCNU, vincristine, alternating with adriamycin and vincristine). Split course radiotherapy (total 45 Gy over 4 weeks) was also given to all patients with limited disease (CALGB 7781) as well as prophylactic brian irradiation. Radiotherapy to the chest was also given in an additional arm of CALGB 7782 for patients with extensive disease. No significant differences were seen for response and survival within categories defined by extent of disease. Overall about 25 per cent of patients achieving complete remission remain alive at 2 years. The prognostic impact of different factors including extent of disease, performance of status, age and sex are discussed.
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PMID:Small cell anaplastic carcinoma of the lung. The Cancer and Leukemia Group B Experience. 628 Jul 94

Based on the concept of "stem-cell competition," hypertransfusion has been shown to attenuate the leucopenia associated with chemotherapy in children with leukemia. We conducted a randomized, controlled study of hypertransfusion in 25 patients with inoperable lung cancer who received combination chemotherapy consisting of methotrexate, adriamycin, cyclophosphamide, and CCNU (Lomustine) (MACC scheme). Twelve patients in the hypertransfusion group were given red cell transfusion to a hemoglobin value greater than or equal to 17 gm/dl prior to each chemotherapy cycle. The two groups of patients were comparable in age, cell type, extent of disease, performance status, and initial hemoglobin level and blood counts. The mean fall in granulocyte count was greater for control group (3.76 X 10(9)/liter) than for hypertransfusion group (3.27 X 10(9)/liter), and the mean fall in platelet count was greater for control group (53.84 X 10(9)/liter) than for hypertransfusion group (35.83 X 10(9)/liter), although the differences did not reach statistical significance (p greater than 0.05) partly because our MACC scheme was probably not sufficiently myelosuppressive to bring about a difference in the two groups. Granulocytopenia-associated infections were infrequent in both groups: two episodes in 37 cycles of chemotherapy in the hypertransfusion group and three episodes in 43 cycles in the control group. Hypertransfusion was simple and safe, and the encouraging trend towards less marked myelosuppression in our hypertransfused group would warrant further studies using more intensive and myelosuppressive combination chemotherapy regimens.
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PMID:Can hypertransfusion attenuate myelosuppression associated with combination chemotherapy in patients with inoperable bronchogenic carcinoma? A report of a randomised, controlled study. 635 98

Chlorozotocin is a glucose-substituted chloroethyl nitrosourea with pharmacologic properties suggesting it is a relatively nonmyelosuppressive cancer chemotherapy drug. Preclinical studies have shown that this drug possesses approximately twice the in vitro alkylating activity of the chloroethyl nitrosoureas BCNU and CCNU. In the L1210 leukemia system, chlorozotocin has curative activity at doses that result in minimal bone marrow toxicity. In vitro studies of human bond marrow stem cells have shown that chlorozotocin is relatively sparing of these cells compared to BCNU. Phase I and phase II trials in man have been performed that show that chlorozotocin's dose-limiting toxicity is thrombocytopenia at doses greater than 120 mg/m2. In the phase II trial, 16% of patients with colon cancer and 20% of patients with malignant melanoma evidenced objective regression of disease. Chlorozotocin is now undergoing phase II evaluation in combination chemotherapy trials in colon and stomach cancer.
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PMID:Preclinical and clinical studies on chlorozotocin, a new nitrosourea with decreased bone marrow toxicity. 644 66

A rationale based on known chemical, biochemical, and biologic properties of nitrosoureas led to the testing of combinations of CCNU with chlorozotocin for in vivo activity against L1210 leukemia. Several combinations yielded synergistic antileukemic activity.
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PMID:Synergistic antileukemic activity of combinations of two nitrosoureas. 645 82

Using our new in vitro antitumor sensitivity assay, the basis of which depends on predictive analysis of morphological findings of L1210 leukemia cells under the influence of antitumor agents, 5 kinds of nitrosoureas including MCNU were comparatively tested for antitumor activity. A cell killing effect became apparent very soon under BCNU and CCNU, rather late under Methyl-CCNU and MCNU, and intermediately under ACNU. Various cellular biological effects were apparently induced in L1210 cells by MCNU and its mechanism of action seemed to be broader than that of any other members of the nitrosoureas.
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PMID:[Antitumor activity of a new nitrosourea, MCNU, on a cellular morphological basis evaluated by a new in vitro antitumor sensitivity assay]. 659 74


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