Cyclophosphamide (CPA) is the most common alkylating antineoplastic agent, as well as a strong immunosuppressant that is frequently applied to autoimmune diseases and organ transplantation. It is metabolized by cytochrome P450 oxidases (CYPs) to its active metabolite which played a critical role in therapy. CPA has serious and even fatal side effects, and its efficacy and adverse reactions are significantly varied among individuals. In this review, the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the disposition of CPA with the efficacy and adverse effects of CPA were summarized, thereby providing fundamental reference for further pharmacogenomic study of CPA.
Antineoplastic Agents, Alkylating ; pharmacology ; Cyclophosphamide ; pharmacology ; Humans ; NADPH-Ferrihemoprotein Reductase ; metabolism ; Pharmacogenetics

This study was aimed to investigate the modulating effects on telomere length and telomerase activity in K562 cells treated by arsenic trioxide, ginseng saponin, beta-elemene alone or in combination with cyclophosphamide (CTX) and to explore the possible mechanism and new therapy for acute leukemia. Human erythroleukemic cell line K562 was co-cultured with the above-mentioned drugs. Cells were collected after 24, 48 and 72 hours for further detection. Telomere length and telomerase activity were detected by Southern-blot and PCR-ELISA respectively. The effects of these drugs were observed at different concentrations and exposure time. The results showed that (1) ginseng saponin, arsenic trioxide, beta-elemene, or CTX could completely inhibit the telomerase activity of K562 cells at proper concentrations and exposure time. The inhibiting effects were enhanced when the three former drugs were used with CTX. Telomerase activity decreased proportionally with the concentrations and length of time. (2) viability of K562 cells was decreased after being co-cultured with arsenic trioxide, ginseng saponin, beta-elemene and CTX. The level of inhibition depends on the concentration and exposure time. (3) telomere length of K562 cells was 5.36 +/- 0.18 kb. After being co-cultured with those drugs for 72 hours, telomere length was 5.90 kb -6.50 kb, significantly longer than that of control (5.18 - 5.35 kb). It is concluded that arsenic trioxide, ginseng saponin, and beta-elemene can inhibit the growth and telomerase activity of K562 cells. The inhibiting effects were enhanced when they were used in combination with CTX. The depression of telomerase activity may be one of the mechanisms of anti-tumor effect. Less dosage and shorter course can be expected when arsenic trioxide, ginseng saponin, and beta-elemene are used in combination with CTX. When telomerase activity was depressed, the telomere length prolonged a little, indicating K562 cell line may extend telomeres by some alternative way other than telomerase activation.
Arsenicals ; pharmacology ; Cyclophosphamide ; pharmacology ; Drug Synergism ; Humans ; K562 Cells ; Oxides ; pharmacology ; Panax ; chemistry ; Saponins ; pharmacology ; Sesquiterpenes ; pharmacology ; Telomerase ; drug effects ; metabolism ; Telomere ; drug effects

No abstract available.
Animals ; Cyclophosphamide/*pharmacology ; Immunosuppressive Agents/*pharmacology ; Lung/*drug effects ; Lung Injury/*drug therapy ; Male ; *Paraquat ; Pulmonary Edema/*drug therapy

OBJECTIVETo investigate the protective effect of epigallocatechin gallate (EGCG) on mouse sperm in vivo.

METHODSA total of 64 six-week-old male Kuming mice were randomly divided into eight groups of equal number to be treated with normal saline (negative control), Cyclophosphamide (CP) at 30 mg/kg (positive control), and CP followed by EGCG (experimental) at 20, 40, and 80 mg/kg, respectively, given every other day for 10 days. At 4 and 5 weeks after treatment, the bilateral testes of the mice were harvested for examination of sperm abnormality.

RESULTSEGCG did not increase the rate of CP-induced sperm abnormality in the mice, but reduced it instead with the prolonged time of treatment.

CONCLUSIONEGCG protects mouse sperm in vivo.

Animals ; Catechin ; analogs & derivatives ; pharmacology ; Cyclophosphamide ; toxicity ; Male ; Mice ; Mutagens ; toxicity ; Random Allocation ; Spermatozoa ; drug effects ; Time Factors

OBJECTIVEComparative study on the immunologic functions of total flavones of Epimedium (TFE) in two species in Guizhou on CTX mice.

METHODTo set up a hypoimmunity mouse model by CTX and give TFE in 10 days, the enhancement of immunologic functions of TFE of two species were observed with the indice of the weight of body and spleen, the spleen-index, the serum level of hemolysin, TNF-alpha and IL-2.

RESULTThe spleen-index, the level of hemolysin, TNF-alpha and IL-2 of the mice decreased apparently (P < 0.01) by single ip in CTX 80 mg x kg(-1). The weight of body and spleen, the spleen-index of the mice increased, the decreased serum level of hemolysin TNF-alpha and IL-2 increased significantly (P < 0.01), by TFE of two species of 1.3, 0.65 g x kg(-1) from the mice ig.

CONCLUSIONThe TFE of two species of Epimedium in Guizhou have an obvious immune enhancement effect on the non-specific immunity and specific immunity of CTX model mice. But the immune enhancement effects of the TFE from the stem and leaves of two species of Epimedium contrast insignificantly. This indicates that in addition to ICA, there must be other bioactive components that can enhance immunity.

Animals ; Cyclophosphamide ; pharmacology ; Epimedium ; chemistry ; Female ; Flavones ; pharmacology ; Immunity ; drug effects ; Interleukin-2 ; blood ; Male ; Mice ; Tumor Necrosis Factor-alpha ; blood

This study evaluates the pathogenesis of rheumatoid arthritis by producing immune complex induced arthritis with an intra-articular injection of BSA in immunized rabbits, and the effect of systemic administration of cyclophosphamide and local administration of anti-macrophage serum. The reduction of inflammatory reaction by cyclophosphamide administration appears to be caused mainly by selective depletion of the neutrophils, and partly by immune suppression. It appears that the rabbit abdominal macrophage has the common morphologic, functional and antigenic patterns with the M-type synovial lining cells. There is another possibility that the cross-reacting antigens between macrophage and the M-type cell of the synovial lining may exist. It is concluded that in this experimental immune complex arthritis, the site of localization of immune complexes seems to be the synovial, M-type cell, and the tissue injury of synovium is largely mediated not only by neutrophils and complement, but also by macrophages.
Animal ; Antigen-Antibody Complex* ; Arthritis, Rheumatoid/etiology* ; Cyclophosphamide/pharmacology ; Immune Complex Diseases/etiology* ; Immune Sera/pharmacology ; Macrophages ; Rabbits ; Serum Albumin, Bovine/administration & dosage ; Synovial Membrane/pathology

OBJECTIVETo study the effect of folic acid cooperating with soybean isoflavone on the oxidative status of neural tube defects (NTDs) pregnant rats induced by cyclophosphamide, to observe the relationship of the two factors, folic acid and the isoflavone and to look for the best co-intervention group.

METHODSThe 100 pregnant rats of 2.5-3 months old were randomly divided into the control group, model group, co-intervention groups and solo-intervention groups. The animals were executed on the 20th day of gestation as to examining the levels of antioxidative indices (GSH, GSH-Px, Se, Mn, Fe) in blood. The incidence rates of NTDs were calculated.

RESULTSThe interaction of folic acid and isoflavone had significant effect on the indices related with antioxidation (P < 0.05). Folic acid 0.7 mg/kg cooperated with isoflavone 160 mg/kg had the best intervention effects in our study. Compared with the solo-intervention by folic acid 1.4 mg/kg and isoflavone 320 mg/kg, the effect of co-intervention (folic acid 0.7 mg/kg cooperated with isoflavone 160 mg/kg) was significantly better (P < 0.05).

CONCLUSIONFolic acid should be the main protective factor of NTDs, and isoflavone might reinforce the protective effects of folic the acid on NTDs by increasing the antioxidative ability, however, the effect is related with the ratio of the two factors.

Animals ; Cyclophosphamide ; Drug Interactions ; Female ; Folic Acid ; pharmacology ; Isoflavones ; pharmacology ; Male ; Neural Tube Defects ; chemically induced ; prevention & control ; Pregnancy ; Rats ; Rats, Wistar ; Soybeans ; chemistry

We chose Hela cells as research object and studied the cytotoxicity generated by cyclophosphamide, an antitumor drug, after cell electroporation by the use of electromagnetic pulses. Comparison between the electroporation group and the contrast group revealed the greatly enhanced cytotoxicity of the electroporation group, indicating that under some conditions electromagnetic pulses can enhance the cytotoxicity of antitumor drugs. The results of this study provide reliable evidences and a feasible approach for clinical treatment of tumor.
Antineoplastic Agents ; pharmacology ; Apoptosis ; Cell Survival ; drug effects ; Cyclophosphamide ; pharmacology ; Drug Screening Assays, Antitumor ; Electromagnetic Phenomena ; Electroporation ; methods ; HeLa Cells ; Humans

OBJECTIVETo observe the protective effects of vitamin E on the testicular injury by cyclophosphamide in mice, and the correlative mechanism.

METHODSFifty sexually mature male mice were randomly divided into five groups: the cyclophosphamide group (the CP group), the low-dose vitamin E group (the low-dose group), the middle-dose vitamin E group (the middle-dose group), the high-dose vitamin E group (the high-dose group), the matched control group (the control group). The first four groups were given cyclophosphamide by gavage at a dose of 5 mg/(kg x d). The low-dose group, the middle-dose group and the high-dose group were given vitamin E by subcutaneous injection at doses of 30 mg/(kg x d), 50 mg/(kg x d) , 70 mg/(kg x d) after 4 h of cyclophosphamide treatment. The control group was gavaged with equivalent normal saline. The treatment period for all groups was 28 days. The level of plasma FSH, LH, T and the activity of testicular SOD, GSHPx, CAT and the level of testicular MDA were detected. The histological structure and the ultrastructure of the testis were examined by light microscope and electron microscope.

RESULTSAs compared with the CP group, the plasma FSH, LH, T level and the SOD, GSHPx, CAT activity in the middle-dose group and the high-dose group were higher (P< 0.05, P< 0.01), MDA level significantly lower(P<0.01). The histological structure and the ultrastructure of the testis were in the normal range.

CONCLUSIONVitamin E has protective effects on the testicular injury by cyclophosphamide in mice. The possible mechanism of vitamin E may be its scavenging free radical and antioxidant effects, as well as it may have some stimulatory effects on gonadotrophin releasing of pituitary anterior lobe.

Animals ; Antioxidants ; pharmacology ; Cyclophosphamide ; antagonists & inhibitors ; toxicity ; Dose-Response Relationship, Drug ; Male ; Mice ; Mice, Inbred Strains ; Random Allocation ; Testis ; drug effects ; pathology ; Vitamin E ; pharmacology

AIMTo study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate the protective effect of ascorbic acid.

METHODSThe testicular D5, 3b-hydroxysteroid dehydrogenase (HSD), 17b-HSD, peroxidase and catalase activities along with the levels of malondialdehyde (MDA) and conjugated dienes in testicular tissue were measured for the evaluation of testicular oxidative stress. The plasma testosterone (T) level was measured by immunoassay. Various germ cells at stage VII of spermatogenic cycle were quantified from testicular stained sections.

RESULTSCyclophosphamide treatment results in a significant inhibition in the testicular D5, 3b-HSD and 17b-HSD activities, a decrease in plasma T level and a diminution in the counts of various germ cells. Moreover, this treatment was also associated with a significant inhibition of the peroxidase and catalase activities along with high levels of MDA and conjugated dienes in the testis. All these changes were reversed by ascorbic acid co-administration.

CONCLUSIONCyclophosphamide treatment at the dosage used caused testicular gametogenic and androgenic disorders as well as induced testicular oxidative stress that can be reversed by ascorbic acid co-administration.

Animals ; Antioxidants ; pharmacology ; Ascorbic Acid ; pharmacology ; Body Weight ; Catalase ; metabolism ; Cyclophosphamide ; pharmacology ; Hydroxysteroid Dehydrogenases ; metabolism ; Infertility, Male ; chemically induced ; drug therapy ; Lipid Peroxidation ; drug effects ; Male ; Mutagens ; pharmacology ; Peroxidase ; metabolism ; Rats ; Rats, Wistar ; Spermatogenesis ; drug effects ; Testosterone ; blood