OBJECTIVETo study genetic damage of workers alone occupationally exposed to methotrexate (MTX) with three end-points.

METHODSThe blood samples from 21 workers exposed to MTX and 21 controls were detected with micronucleus test, comet assay, hprt gene mutation test and TCR gene mutation test.

RESULTSThe mean micronuclei rate (MNR) and mean micronucleated cells rate (MCR) in 21 workers were 10.10 per thousand +/- 0.95 per thousand and 8.05 per thousand +/- 0.75 per thousand, respectively, which were significantly higher than those (5.48 per thousand +/- 0.82 per thousand and 4.38 per thousand +/- 0.58 per thousand) in control (P < 0.01). The mean tail length (MTL) of 21 workers and 21 controls were (1.30 +/- 0.06) microm and (0.07 +/- 0.01) microm, respectively, there was significant difference between workers and controls (P < 0.01). But the difference between workers and controls for mean tail moment (MTM) was not significant (P > 0.05). The average mutation frequency (Mf-hprt) of hprt and (Mf-TCR) of TCR in workers were 1.00 per thousand +/- 0.02 per thousand and (6.87 +/- 0.52) x 10(-4), respectively, which were significantly higher than those [0.86 per thousand +/- 0.01 per thousand and (1.67 +/- 0.14) x 10(-4)] in control (P < 0.01).

CONCLUSIONThe genetic damage to some extent appeared in workers occupationally exposed to methotrexate.

Adult ; Comet Assay ; DNA Damage ; Female ; Humans ; Hypoxanthine Phosphoribosyltransferase ; genetics ; Male ; Methotrexate ; toxicity ; Micronucleus Tests ; Middle Aged ; Mutation ; Occupational Exposure

Methotrexate(MTX) is a commonly used antimetabolite, which can be used in the treatment of a variety of diseases. However, hepatotoxicity in the use of MTX severely limits its clinical use. Therefore, how to prevent and treat hepatotoxicity of MTX has become an urgent clinical problem. This paper summarizes and analyzes relevant literatures on the prevention and treatment of hepa-totoxicity caused by MTX with traditional Chinese medicines and natural medicines in recent years. MTX-induced hepatotoxicity mechanisms include folate pathway, oxidative stress damage and adenosine pathway, of which oxidative stress theory is the main research direction. A total of 14 kinds of traditional Chinese medicine and natural medicine extracts including white peony root, and 21 kinds of natural monomer compounds, including berberine, play an anti-MTX-induced hepatotoxic effect by resisting oxidative stress, inhibiting inflammation and regulating signal pathways. According to current studies on the prevention and treatment of hepatotoxicity induced by MTX with traditional Chinese medicines and natural medicines, there are insufficiencies, such as partial and superficial mechanism studies, inadequate combination of experimental research and clinical practice, non-standard experimental design and lack of application of advanced technologies and methods. This paper systematically reviewed the effects and mechanisms of traditional Chinese medicines and natural medicines against hepatotoxicity induced by MTX and defined current studies and deficiencies, in the expectation of proposing new study strategies and directions and providing scientific basis for rational clinical use of MTX and development of new drugs against MTX hepatotoxicity.
Chemical and Drug Induced Liver Injury/prevention & control* ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Liver/metabolism* ; Medicine, Chinese Traditional ; Methotrexate/toxicity* ; Oxidative Stress

Acute Disease ; Antimetabolites, Antineoplastic ; adverse effects ; toxicity ; Drug-Related Side Effects and Adverse Reactions ; Female ; Folic Acid Antagonists ; therapeutic use ; Humans ; Methotrexate ; adverse effects ; toxicity ; Middle Aged ; Nausea ; chemically induced ; Risk Factors ; Skin Diseases ; chemically induced ; Vomiting ; chemically induced

OBJECTIVETo study the effect of methotrexate (MTX), a folic acid antagonist which can lead to folic acid deficient, on the cardiac development and on the expressions of BMP2b and HAS2 in zebrafish.

METHODSThe zebrafish embryos at 6-48 hrs post fertilization (hpf) were treated with various concentrations of MTX (0.5 x 10(-3), 1.0 x 10(-3) and 2.0 x 10(-3) M). At 48 hpf, the percentage of cardiac malformation and heart rate were recorded. The zebrafish embryos at 6-10 hpf treated with 1.5 x 10(-3) M MTX were used as the MTX treatment group. At 24 and 48 hpf the cardiac morphology was observed under a microscope. The expressions of BMP2b and HAS2 in zebrafish were detected by in situ antisense RNA hybridization and real-time PCR.

RESULTS6-12 hpf, the early embryonic developmental stage, was a sensitive period that MTX affected cardiac formation of zebrafish. The retardant cardiac development and the evidently abnormal cardiac morphology was found in the MTX treatment group. The results of in situ antisense RNA hybridization showed that the expressions of BMP2b and HAS2 in the zebrafish heart were reduced in the MTX treatment group at 36 and 48 hpf. The real-time PCR results demonstrated that the BMP2b expression decreased at 12, 24, 36 and 48 hpf, and that the HAS2 expression decreased at 24, 36 and 48 hpf in the treatment group compared with the control group without MTX treatment.

CONCLUSIONSThe inhibition of folic acid function may affect cardiac development of early embryos, resulting in a retardant development and a morphological abnormality of the heart in zebrafish, possibly by down-regulating the expressions of BMP2b and HAS2.

Abnormalities, Drug-Induced ; etiology ; Animals ; Bone Morphogenetic Protein 2 ; Bone Morphogenetic Proteins ; genetics ; Down-Regulation ; Folic Acid Antagonists ; toxicity ; Gene Expression Regulation ; drug effects ; Glucuronosyltransferase ; genetics ; Heart Defects, Congenital ; chemically induced ; Hyaluronan Synthases ; Methotrexate ; toxicity ; Polymerase Chain Reaction ; Zebrafish ; Zebrafish Proteins ; genetics

OBJECTIVETo explore the therapeutic effect of interleukin-11 (IL-11) on high-dose methotrexate (HDMTX) induced mucositis in Wistar's rats, the proliferative effect on CEM leukemia cell line and the antitumor effect on HDMTX.

METHODSNinety-five 5-week old, 120 - 150 grams weight Wistar rats were randomly divided into five groups. Group A is normal control (n = 15), group B MTX control (n = 20), group C IL-11 pretreatment group before MTX injection (n = 20), group D (n = 20) the high dose IL-11 group (475 microg.kg(-1).d(-1)) after MTX injection, group E (n = 20) the low dose IL-11 group (150 microg.kg(-1).d(-1)) after MTX injection. All rats in group B approximately E were given 1 ml MTX intraperitoneally (100 mg/kg). Rats were killed at day 1, 3, 5, 7 after MTX injection. The mortality rates, changes of small intestine tissue morphology and ultra structure were observed. The proliferation of small intestine crypt cell was assayed by proliferating cell nuclear antigen (PCNA) immunohistochemical staining. MTT method was used to detect the proliferation of CEM cell line.

RESULTIL-11 treatment resulted in a significant increase of survival of HDMTX treated rats, increased of small intestinal villus length and villus/crypt ratio. IL-11 administration was associated with enhancement of small intestine mucosa recovery after HDMTX therapy. Group C showed a greater effect than group B (P < 0.01). IL-11 had no effect on CEM cell proliferation.

CONCLUSIONIL-11 has a significant mitigating effect on high-dose MTX induced intestinal mucositis in rat, and significantly increase the survival of the rats. IL-11 could be safely used in the HDMTX treatment of childhood acute lymphocyte leukemia.

Animals ; Antimetabolites, Antineoplastic ; toxicity ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Cell Survival ; drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Humans ; Immunohistochemistry ; Interleukin-11 ; pharmacology ; therapeutic use ; Intestinal Mucosa ; drug effects ; pathology ; ultrastructure ; Intestine, Small ; drug effects ; metabolism ; pathology ; Male ; Methotrexate ; toxicity ; Microscopy, Electron ; Mucositis ; chemically induced ; mortality ; prevention & control ; Proliferating Cell Nuclear Antigen ; analysis ; Random Allocation ; Rats ; Rats, Wistar ; Survival Rate