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)

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

Mitoxantrone (1,4-dihydroxy-5,8-bis[[2-[(2-hydroxyethyl)amino]ethyl]amino]-9,10-anthracenedione dihydrochloride) in animal studies appears to have a mechanism of action and broad antitumor spectrum similar to the anthracyclines and in preliminary animal studies is without cardiotoxicity. To determine the maximally tolerated dose, mitoxantrone was given to 25 patients with various advanced solid tumors. Sixteen patients had received prior doxorubicin and/or lomustine (CCNU). Myelosuppression was the major toxic effect. All 13 patients who received mitoxantrone doses greater than or equal to 2.73 mg/m2 x 5 days experienced moderate (2000--3000 cells/mm3) or severe (less than 2000 cells/mm3) leukopenia. Thrombocytopenia was also encountered in three of these 13 patients (severe in one, less than 50,000 cells/mm3). At dose levels less than 2.73 mg/m2 x 5 days, myelosuppression was seen in four of 12 patients (three with mild leukopenia and one with mild thrombocytopenia). The blood cell count nadir occurred at 10 days and full recovery occurred by Day 21. Minor clinically insignificant ECG changes occurred in five patients. Minor and transient antitumor effects were seen in five patients. The maximum tolerated dose of mitoxantrone over a 5-day course is 2.73 mg/m2, with leukopenia being the limiting toxic effect.
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PMID:Phase I study of a 5-day schedule of mitoxantrone (dihydroxyanthracenedione). 708 34