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PubMed2002

Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats.

Cyclophosphamide is an inactive cytostatic, which is metabolised into active metabolites mainly in the liver. During bioactivation, reactive oxygen species (ROS) are also formed, which can modify the components of both healthy and neoplastic cells leading to decreased antioxidative capacity. Amifostine is a drug that can inactivate ROS. The aim of the present study was to evaluate the influence of amifostine on the antioxidative system of the liver of rats exposed to cyclophosphamide. Intraperitoneal administration of cyclophosphamide was found to decrease the activity of liver antioxidative enzymes, i.e. superoxide dismutase, glutathione peroxidase and glutathione reductase, and to increase catalase activity. Amifostine slightly influenced antioxidative enzyme activity, causing a significant increase only in superoxide dismutase activity. Co-administration of cyclophosphamide and amifostine nearly prevented changes in activities of superoxide dismutase, glutathione reductase and catalase, as well as to a high degree of glutathione peroxidase. Cyclophosphamide also evoked a decrease in the level of non-enzymatic antioxidants, such as reduced glutathione and vitamins C, E and A, as well as total antioxidant status. Administration of amifostine alone caused a significant increase in non-enzymatic antioxidant level that resulted in an increase in total antioxidant status. Administration of amifostine together with cyclophosphamide to a large extent prevented changes in the evaluated non-enzymatic antioxidative parameters, decreasing values of their concentration to the values of control group. Changes of liver antioxidative abilities during detoxification of cyclophosphamide were accompanied by intensified lipid peroxidation, manifested by an increase in concentration of products such as malondialdehyde and 4-hydroxynonenal. Amifostine caused the inhibition of lipid peroxidation in the liver of both control and cyclophosphamide-treated rats. In conclusion, our results suggest that amifostine significantly protects liver antioxidant properties from changes caused by cyclophosphamide treatment and in consequence prevents oxidative stress and phospholipid peroxidative damage.

Amifostine↗

PubMed1995

Effect of cyclophosphamide administration on the activity and relative content of hepatic P4502D1 in rat.

1. The effects of the administration of the anticancer and immunosuppressive drug, cyclophosphamide, to the rat on hepatic P4502D1 activity and content in the microsomal fraction have been examined. 2. Liver microsomes were obtained from male Hooded Wistar rats administered a single dose (i.p.) of saline or cyclophosphamide (200 mg/kg). Rats receiving cyclophosphamide were killed 1, 4, 7, 10 or 14 days after cyclophosphamide administration. The O-demethylation of dextromethorphan to dextrorphan was used to monitor 2D1 activity. 3. The mean Vmax for dextrorphan formation was reduced significantly (p < 0.0001) 7, 10 and 14 days after cyclophosphamide administration compared with the control group (control, 0.32 +/- 0.07; 7-day, 0.20 +/- 0.08; 10-day, 0.11 +/- 0.02; and 14-day group, 0.15 +/- 0.02 nmol/mg/min). 4. Western blotting revealed that there was a significant reduction (p < 0.0005) in the microsomal relative 2D1 content 10 days after cyclophosphamide administration compared with the control group (control, 1.25 +/- 0.44; and 10-day group, 0.65 +/- 0.14). 5. The activity of reduced nicotinamide adenine dinucleotide phosphate P450 reductase was significantly reduced (p < 0.0001) 7, 10 and 14 days following cyclophosphamide administration (control, 215 +/- 24; 7-day, 102 +/- 20; 10-day, 59 +/- 4 and 14-day group, 76 +/- 8 nmol/mg/min). Cytochrome b5 content was significantly reduced (p < 0.0001) 7 and 10 days following cyclophosphamide administration (control, 0.46 +/- 0.13; 7-day, 0.28 +/- 0.07 and 10-day group, 0.20 +/- 0.03 nmol/mg). 6. The significant reductions in the activity of rat hepatic microsomal 2D1 following cyclophosphamide administration, as seen by the alterations in mean Vmax for dextrorphan formation, do not appear to be due to a single factor, but may result from a combination of several events, including reductions in relative 2D1 content, reduced nicotinamide adenine dinucleotide phosphate P450-reductase activity and cytochrome b5 content.

Animals↗

PubMed2006

Different mechanisms for anti-tumor effects of low- and high-dose cyclophosphamide.

It is known that, besides its direct cytotoxic effect as an alkylating chemotherapeutic agent, cyclophosphamide also has immuno-modulatory effects, such as depletion of CD4+CD25+ regulatory T cells. However, its optimal concentration has not yet been fully elucidated. Therefore, we first compared the effects of different doses of cyclophosphamide on T cell subsets including CD4+CD25+ T cells in mice. Cyclophosphamide (20 mg/kg) decreased the numbers of splenocytes, CD4+ and CD8+ T cells by approximately 50%, while a decline in CD4+CD25+ T cell number was more profound, leading to the remarkably lower ratios of CD4+CD25+ T cells to CD4+ T cells. In contrast, 200 mg/kg cyclophosphamide severely decreased the numbers of all the T cell subsets by > 90% although the decreased ratios of CD4+CD25+ T cells to CD4+ T cells were still observed. Next, low-dose cyclophosphamide significantly inhibited in vivo growth of murine hepatoma MH129 tumor in immuno-competent but not immuno-deficient mice. This anti-tumor effect was abolished by CD4+CD25+ T cell repletion. In contrast, high-dose cyclophosphamide exhibited similar anti-tumor effects in both mice. In addition, contrary to antibody-mediated CD4+CD25+ T cell depletion, administration of low-dose cyclophosphamide after tumor inoculation was more efficacious than the prior administration. Our data show that low-dose cyclophosphamide selectively depletes CD4+CD25+ T cells, leading to enhanced anti-tumor effects against pre-existing tumors, while the anti-tumor effect of high-dose cyclophosphamide is solely attributed to its direct cytotoxicity. These findings appear to be highly crucial in a clinical setting of combined chemotherapy and immunotherapy for cancer treatment.

Animals↗

PubMed1991

Lack of effect of cyclophosphamide on the immunogenicity of a melanoma antigen vaccine.

Melanoma antigen vaccines are a conceptually attractive approach to prevent or delay disease recurrence in patients with surgically resected malignant melanoma. However, the immunogenicity of current vaccines is relatively low. Cyclophosphamide, when given in low doses prior to antigen exposure, is an immunomodulator which has been shown to enhance both humoral and cellular antitumor responses in animals and humans. We conducted a prospective, randomized, clinical trial to study whether pretreatment with cyclophosphamide augments the immunogenicity of a polyvalent, allogeneic, melanoma antigen vaccine in patients with melanoma and low tumor burden. Forty-five patients with resected stage II melanoma (regional metastases) were randomly allocated to treatment with melanoma vaccine or melanoma vaccine plus cyclophosphamide. All patients received the same dose and schedule of vaccine immunizations; those randomized to cyclophosphamide received 300 mg/m2 i.v. 3 days prior to each vaccine immunization. Cellular immune responses were evaluated by delayed-type hypersensitivity (DTH) skin reactivity to a test dose of vaccine at baseline (prior to treatment) and following the fourth immunization. Humoral immune responses were measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiographic analysis of indirect immunoprecipitates of patients' sera at the same time points. Twenty-four patients were randomized to cyclophosphamide pretreatment and 21 to vaccine alone; 22 and 18 patients were evaluable in each group, respectively. Differences were statistically nonsignificant with respect to either cellular (DTH) or humoral (antibody) responses between the two groups. DTH responses were induced in 16 of 22 (73%) and 15 of 18 (83%) patients treated with cyclophosphamide plus vaccine and vaccine alone, respectively. The mean posttreatment augmentation in DTH response in the cyclophosphamide group was 9.5 mm, compared with 9.9 mm in the vaccine-only group. Eight of 12 (66%) cyclophosphamide-pretreated patients and 9 of 12 (75%) vaccine-only patients produced increased titers of antimelanoma antibodies following treatment. No differences were observed between the groups in disease-free or overall survival. In summary, low-dose cyclophosphamide pretreatment failed to augment the immunogenicity of a polyvalent, allogeneic, melanoma vaccine in patients with completely resected early-stage melanoma.

Adult↗

PubMed1989

Tumor-infiltrating lymphocytes cultured in recombinant interleukin-2: enhancement of growth, cytotoxicity, and phenotypic expression of cytotoxic T-cell antigens by cyclophosphamide given intravenously prior to tumor harvest.

Tumor-infiltrating lymphocytes (TILs) have potent antitumor effects in murine models of advanced disease. Although these cells are 50-100 times more potent than lymphokine-activated killer cells against micrometastases, their antitumor benefits are virtually nonexistent against large tumor burdens unless cyclophosphamide is added to the immunotherapy regimen. In an effort to determine the effects of cyclophosphamide on TILs obtained from tumor-bearing animals, we harvested tumors from animals having received either 0, 50, or 100 mg/kg cyclophosphamide intravenously and investigated the expansion, cytotoxicity, and phenotypic expression of these TILs co-cultured in vitro with recombinant interleukin-2. TILs obtained from animals given cyclophosphamide, demonstrated a greater fold expansion than TILs obtained from normal animals (mean fold expansion on day 59 of culture: 85, 400, and 150 for TILs obtained from animals given 0, 50, and 100 mg/kg cyclophosphamide, n = 3 consecutive experiments). In addition, these TILs demonstrated enhanced cytotoxicity compared to controls [effector to target ratio 4:1, day 16 TILs, % lysis: 24, 35, and 45%, cyclophosphamide 0, 50, and 100 mg/kg, respectively, against the MCA-102 sarcoma, natural killer (NK) insensitive tumor; 29, 38, and 56% against the YAC-1 lymphoma, NK sensitive tumor]. Similar results were seen with day 34 and day 59 TILs. When phenotypic analysis was performed, TILs obtained from animals given cyclophosphamide consistently demonstrated a greater percent expression of the Thy1.2 and Lyt-2 antigens up to day 59 of culture when the experiments were terminated. The NK cell marker 49H.8 was expressed on the majority of TILs and its expression did not change with respect to the cyclophosphamide concentration. The increase in TIL number and cytotoxicity seen with cyclophosphamide given intravenously before tumor harvest could have important ramifications for human immunotherapy with TILs.

Animals↗

PubMed1995

Evaluation of effects of chitosan in preventing hemorrhagic cystitis in rats induced by cyclophosphamide.

Hemorrhagic cystitis is a common problem following cyclophosphamide or radiation therapy. Chitosan has been shown to be an effective hemostatic agent and promoter of wound healing in animal experiments. We evaluated the safety and efficacy of intravesical chitosan in an animal model of cyclophosphamide cystitis. Hemorrhagic cystitis was induced in female F344 rats by intraperitoneal cyclophosphamide, 100 mg/kg. Chitosan solution (0.3 ml) was instilled intravesically on day 1 (Group 1), on days 1, 3, and 5 (Group 2), or 1 hour after the administration of cyclophosphamide (Group 3). The rats in group 4 were treated with chitosan diluent on day 1 after cyclophosphamide, and the rats in group 5 received intravesical chitosan without cyclophosphamide. Sequential examination revealed decreased mortality and lower incidences of severe bladder bleeding, necrosis and inflammation in Group 3. Treatment delayed until after the appearance of the cystitis, especially repeated treatments, appeared to make the cyclophosphamide-induced changes worse. Used within 1 hour of cyclophosphamide administration, before the cystitis develops, chitosan seemed to have the possibility to inhibit the appearance of hemorrhagic cystitis. In addition to the changes in the bladder, severe changes occurred in the kidneys secondary to cyclophosphamide.

Administration, Intravesical↗

PubMed1998

Effects of cyclophosphamide on maturation and subsequent fertilizing capacity of pig oocytes in vitro.

This study examines the effects of cyclophosphamide, a widely used anti-cancer agent, on the maturation of pig oocytes and on their subsequent fertilizing capacity in vitro. Pig cumulus-oocyte complexes collected from prepubertal gilts were cultured in Waymouth MB 752/1 medium supplemented with sodium pyruvate (50 micrograms/ml), luteinizing hormone (0.5 microgram/ml), follicle-stimulating hormone (0.5 microgram/ml), and 17 beta-estradiol (1 microgram/ml) in the presence or absence of cyclophosphamide for 24 hr; they then were cultured without hormonal supplements in the presence or absence of cyclophosphamide for an additional 16-24 hr. The breakdown of germinal vesicle (GVBD) and changes in glutathione (GSH) content before in vitro fertilization were assessed. Oocytes containing one polar body and a metaphase plate were regarded as matured. Cytoplasmic maturation as determined by male pronuclear formation following fertilization in vitro was also examined. Treatment of oocytes with increasing concentrations (1-1000 micrograms/ml) of cyclophosphamide for 48 hr resulted in a dose-response inhibition of the rate of maturation, but had no effect on GVBD. Increasing duration (12-48 hr) of treatment with cyclophosphamide (100 micrograms/ml) led to a time-dependent inhibition of nuclear maturation, achieving statistical significance by 24 hr. The addition of cyclophosphamide (100 micrograms/ml) to maturation medium immediately after culture, 12 hr or 24 hr after culture also decreased the percentage of oocytes matured during a 48-h culture period. Exposure of oocytes to cyclophosphamide (100 micrograms/ml) for 40 hr did not prevent sperm penetration, not affect the incidence of polyspermy, or decrease the ability of oocytes to form a male pronucleus at 8 hr after insemination. The concentration of GSH, an important factor for male pronuclear formation, in pig oocytes was determined by an enzymatic cycling assay. The concentration found was 8.15 +/- 1.19 mM per oocyte. Exposure of oocytes to cyclophosphamide (100 micrograms/ml) had no effect on GSH concentration. These results demonstrate that cyclophosphamide directly inhibits the meiotic but not cytoplasmic maturation of pig oocytes in vitro. This inhibitory effect, apparently, is not mediated through a decrease in the level of intracellular glutathione.

Animals↗

PubMed1980

Solid tumor models for the assessment of different treatment modalities. XIII. Comparison of response and recovery of host and solid tumor to cyclophosphamide and radiation.

A study of the effects of local tumor radiation alone (1500R) and cyclophosphamide alone (150 mg/kg) on the experimental solid tumor rat hepatoma 3924A has been completed. Cyclophosphamide was more effective in controlling tumor growth than either radiation or 5-fluorouracil (5-FU) (150 mg/kg) previously reported. Parallel recovery of bone marrow with increasing animal survival in "split dose" cyclophosphamide toxicity studies (as with 5-FU) indicates that bone marrow is the critical organ for sequential chemotherapy. Recovery of intestinal mucosa following cyclophosphamide (and 5-FU) occurred much earlier than recovery of bone marrow, substantiating the fact that bone marrow is the critical organ governing the time of administration of a second series of chemotherapeutic agents. The longest period of time (seven days) between delivery of radiation and administration of cyclophosphamide resulted in the most effective use of the two modalities. Tumor growth delay was 1.2 times greater than the additive effects of each agent given alone. Radiation and cyclophosphamide given at other time intervals resulted in either an additive or less than additive effect. One of the greatest difficulties to overcome in the more effective clinical use of combined modality therapy is increased toxicity. In these studies, the least host toxicity occurred when the effects of combined radiation and cyclophosphamide on the tumor were greatest. Results of experimental studies to date suggest that sequential combined modality therapy may be given at a time of maximum tumor growth rate that occurs following the previous treatment series. Since the time of maximum tumor growth rate occurs after recovery of the bone marrow from the previous treatment series, combined chemotherapy-radiotherapy schedules of this type should permit sequential administration of chemotherapeutic agents, such as 5-FU and cyclophosphamide, at the time of enhanced tumor sensitivity and diminished host toxicity.

Animals↗

PubMedDate not supplied

Effects of cyclophosphamide on selected cytosolic and mitochondrial enzymes in the epididymis of the rat.

The anticancer and immunosuppressive drug cyclophosphamide is extensively used in clinical practice and is known to alter fertility in man. We showed previously that treatment of male rats with low daily doses of cyclophosphamide over a 9-week period caused fetal malformations, a high rate of postimplantation loss and affected epididymal and sperm histology. In the present study, five biochemical measures of epididymal function were used to characterize further the effects of cyclophosphamide on the epididymis. For 1, 3, 6, or 9 weeks, adult Sprague-Dawley rats were gavage-fed daily with saline (control), 5.1 (low dose), or 6.8 (high dose) mg/kg of cyclophosphamide. The specific activities of the two glycolytic enzymes aldolase and lactate dehydrogenase (LDH), the mitochondrial enzyme succinate dehydrogenase, the cytosolic enzyme carnitine acetyltransferase and the lysosomal enzyme acid phosphatase were determined in cytosolic and mitochondrial subcellular fractions from four segments of the epididymis. Cyclophosphamide caused decreases in protein concentrations in all segments of the epididymis only after 6 weeks of treatment with the high dose. The specific activities of aldolase, LDH and succinate dehydrogenase did not differ from control with respect to dose or duration of treatment. In contrast, there were significant effects of cyclophosphamide on carnitine acetyltransferase and acid phosphatase specific activity. After 1 week of treatment, there was a transient dose-related decrease in the specific activity of carnitine acetyltransferase, which was most striking for the corpus epididymidis (76% of control), but which did not differ from control after 3, 6, and 9 weeks. After 6 weeks of treatment with the high dose of cyclophosphamide, carnitine acetyltransferase specific activity in the initial segment and the corpus epididymidis was elevated to 165 and 140%, respectively, as compared with the 1-week high dose values. The specific activity of acid phosphatase did not differ from control after 1 and 9 weeks of treatment. At 3 and 6 weeks, however, there was a dose-related increase in acid phosphatase specific activity for all regions of the epididymis that was most marked in the cauda after the 6-week treatment (140% of control). Therefore, low dose, daily treatment of male rats with cyclophosphamide not only alters specific enzymes in specific segments of the epididymis, but acts in a dose- and time-dependent manner. It is possible that these changes could be mediated by direct, toxic effects of the drug on the epithelium or be secondary to alterations in the spermatozoa as a result of the treatment.

Acid Phosphatase↗

PubMedDate not supplied

Spermiogenic germ cell phase-specific DNA damage following cyclophosphamide exposure.

The production of genetically competent spermatozoa is essential for normal embryo development. The chemotherapeutic drug cyclophosphamide creates cross-links and DNA strand breaks in many cell types, including germ cells. This study assessed the phase specificity of the susceptibility of spermiogenic germ cells to genetic damage induced by cyclophosphamide. Adult male rats were given cyclophosphamide using one of four schedules: 1) high dose/acute- day 1, 100 mg/kg; 2) low dose/subchronic, 4 days-days 1-4, 6.0 mg/kg/d; 3) high dose/subchronic, 4 days-day 1, 100 mg/kg, and days 2-4, 50 mg/kg/d; and 4) low dose/chronic-daily, 6.0 mg/kg/d for 14-28 days. To capture cauda epididymal spermatozoa exposed to cyclophosphamide during late, mid-, and early spermiogenesis, animals were sacrificed on days 14, 21, and 28, respectively. Spermatozoa were analyzed for DNA strand breaks using the comet assay. No dramatic increases in damage were seen after high-dose/acute exposure to cyclophosphamide. Subchronic exposure showed a dose-related increase in DNA damage; maximal damage, as demonstrated by comet tail parameters, was seen after 21 days, reflecting an increased susceptibility of step 9-14 spermatids. Low-dose chronic exposure to cyclophosphamide induced DNA damage, which reached a plateau by day 21. The magnitude of damage at all time points after low-dose chronic exposure was much greater than that following low-dose exposure for 4 days, indicating an accumulation of damage over time. Thus, the DNA damage induced by cyclophosphamide is germ cell phase-specific. The most damaging effects of cyclophosphamide occurred during a key point of sperm chromatin remodeling (histone hyperacetylation and transition protein deposition). We speculate that strand breaks disrupt chromatin remodeling, hence affecting chromatin structure and embryo development.

Animals↗

PubMed2002

Potentiation of the antitumour effect of cyclophosphamide in mice by thalidomide.

PURPOSE: Thalidomide has recently shown significant promise in the treatment of some types of cancer, and trials in combination with conventional chemotherapy are being undertaken. We wished to determine whether thalidomide potentiated the effect of cyclophosphamide, a commonly used cytotoxic drug, in a murine tumour model. METHODS: C57Bl/6 mice implanted with subcutaneous Colon 38 tumours were treated with cyclophosphamide alone or together with thalidomide as a single intraperitoneal injection and tumour growth was measured. Concentrations of cyclophosphamide, 4-hydroxycyclophosphamide, 4-ketocyclophosphamide and 2-dechloroethylcyclophosphamide were determined in plasma, liver and tumour tissue using coupled high-performance liquid chromatography-mass spectrometry at different times after treatment. RESULTS: Cyclophosphamide alone (220 mg/kg) induced growth delays of 11-13 days with no cures, whereas cyclophosphamide together with thalidomide (100 mg/kg) cured mice of their tumours. Thalidomide at lower doses (1-20 mg/kg) also potentiated the antitumour effect. Coadministration of thalidomide (100 mg/kg) dramatically decreased the clearance of cyclophosphamide and its metabolites from plasma and tissue, with corresponding increases in the area under the concentration-time curves. The magnitude of the effect was dependent on the dose of thalidomide over the range 1-20 mg/kg with no further effect at a dose of 100 mg/kg. CONCLUSIONS: Coadministration of thalidomide and cyclophosphamide gave markedly greater activity against Colon 38 tumour compared with either drug alone. Investigation of the reason for this effect revealed thalidomide to possess the novel property of dramatically decreasing the clearance of cyclophosphamide and its metabolites.

Animals↗

PubMed2004

Modulation of thalidomide pharmacokinetics by cyclophosphamide or 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice: the role of tumour necrosis factor.

PURPOSE: There is considerable current interest in the use of thalidomide as a single agent or in combination with drugs such as cyclophosphamide in the treatment of multiple myeloma and other cancers. Our previous work has shown that thalidomide potentiates the antitumour activity of both cyclophosphamide and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against murine Colon 38 tumours. In both of these cases, thalidomide extends the half-life (t(1/2)) of the other drug. We wished to determine whether cyclophosphamide and DMXAA altered the t(1/2) of thalidomide. Since both thalidomide and DMXAA modulate tumour necrosis factor (TNF), we also wished to determine the role of TNF in this interaction. METHODS: Mice with Colon 38 tumours were treated with cyclophosphamide (220 mg/kg) and/or thalidomide (20 mg/kg) or DMXAA (25 mg/kg) and thalidomide (100 mg/kg), combinations that have previously demonstrated synergistic activity. Plasma and tumour tissue drug concentrations were analysed by high-performance liquid chromatography. To determine the role of TNF, similar experiments were performed using mice defective in the TNF gene (TNF(-/-)) or the TNF receptor-1 gene (TNFR1(-/-)). RESULTS: Coadministration of cyclophosphamide increased the thalidomide t(1/2) by 3.9- and 3.6-fold, respectively, in plasma and tumour tissue, with a corresponding increase in the concentration-time curve (AUC). The corresponding values following coadministration of DMXAA were 3.0- and 4.6-fold, respectively. Coadministration of cyclophosphamide had similar effects on thalidomide t(1/2) in C57Bl/6, TNF(-/-) and TNFR1(-/-) mice, while coadministration of DMXAA did not alter the t(1/2) or AUC in TNF(-/-) and TNFR1(-/-) mice. CONCLUSIONS: Both cyclophosphamide and DMXAA have a pharmacokinetic interaction with thalidomide, increasing t(1/2) and AUC. TNF mediates the effect of DMXAA on thalidomide pharmacokinetics but not that of cyclophosphamide.

Animals↗

PubMed2004

Cyclophosphamide treatment in systemic necrotizing vasculitis and lupus nephritis. How long? How much?

The gold standard for inducing remission in systemic necrotizing vasculitis (SNV) and severe lupus nephritis is (and remains) the combination of cyclophosphamide and glucocorticoids. Long-term treatment with cyclophosphamide is limited because of toxicity. Recent prospective studies in antineutrophil cytoplasmic antibody (ANCA)-associated SNV revealed that after achievement of clinical remission (usually within 3-4 months after starting cyclophosphamide) cyclophosphamide can be replaced by azathioprine with no increase in relapse rates if treatment is continued for at least 1 year. Methotrexate is inferior to cyclophosphamide because of increased relapse rates-particularly in those with renal involvement-during follow-up. An ongoing study comparing mycophenolate mofetil (MMF) with azathioprine will clarify whether MMF is as successful as azathioprine or even better. The concomitant use of tumor necrosis factor (TNF)-alpha blockers increases the efficacy of immunosuppression. TNF-alpha blockers may be added if SNV is refractory to standard immunosuppressive therapy. However, with this addition to therapy, systemic infections are more frequent. In patients with severe lupus nephritis (WHO IV) the efficacy of combined i.v. therapy with cyclophosphamide and glucocorticoids was shown by NIH trials. This NIH regimen competes with the EURO-Lupus nephritis schedule with a lower dose of i.v. cyclophosphamide followed by maintenance therapy with azathioprine. Long-term follow-up is, however, still lacking in the EURO-Lupus trial. Ongoing prospective studies will reveal whether cyclophosphamide may be substituted by MMF from the very beginning or whether MMF is superior to azathioprine during maintenance therapy of lupus nephritis.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed2005

Infection in children with lupus nephritis receiving pulse and oral cyclophosphamide therapy.

Infection is the major complication of cyclophosphamide therapy in patients with lupus nephritis. The objectives of this study were to report and compare the rate of infection between children with lupus nephritis who had received intravenous pulse cyclophosphamide (IVCY) and those who had received oral cyclophosphamide (OCY) and to determine the risk factors for infection during treatment with cyclophosphamide in these groups. Records of nine patients who had received IVCY from the beginning [pure intravenous cyclophosphamide (PIVCY) group], 11 patients who had received prior oral cyclophosphamide and later switched to IVCY [combined intravenous cyclophosphamide (CIVCY) group] and 41 patients who had received OCY were reviewed. Infection occurred in 21 of 61 patients (34%). In the PIVCY group, four episodes of infection occurred in three of nine patients (33%). In the CIVCY group, six episodes of infection occurred in four of 11 patients (36%). In the OCY group, 18 episodes of infection occurred in 14 of 41 patients (34%). The rate of infection between these groups was not different (P=0.99). None of the following parameters were risk factors for infection: cumulative dose of cyclophosphamide, leukopenia and neutropenia. On the contrary, white blood cell (WBC) count and polymorphonuclear cell (PMN) count were significantly less in the no-infection group (P=<0.001, P<0.001, respectively), with odds ratios for leukopenia (WBCs <4,000 mm(3)) and neutropenia (PMNs <1,500 mm(3)) between the infection and the no-infection group equal to 0.18 (95%CI 0.05-0.63) and 0 (95%CI 0-0.19), respectively. Most of the patients who had infection received prednisolone at a dosage of more than 0.5 mg/kg per day (67% of the PIVCY group, 50% of the CIVCY group and 83% of the OCY group). Fatal infections occurred in two patients who had concomitant active systemic lupus erythematosus (SLE). Although lymphopenia (lymphocyte count <1,500/mm(3)) was not the risk factor for infection, it was observed that six of seven patients with herpes zoster had lymphopenia. Herpes zoster seemed to occur more frequently in the OCY group (15%) than in the whole IVCY group (5%), but there was no statistical difference (P=0.41). We conclude that the rate of infection in the IVCY and OCY group was not different. Infection is likely to occur in patients receiving a concomitant high dose of prednisolone. The occurrence of fatal infection in patients with active disease should be noted. No single risk factor was detected in this study.

Administration, Oral↗

PubMed2006

Steroid-resistant nephrotic syndrome: the influence of race on cyclophosphamide sensitivity.

Steroid-resistant (SR) forms of nephrotic syndrome (NS) have a poorer outcome in blacks compared to other racial groups. In this study, 223 children with SRNS, aged 1-16 years old, were analysed retrospectively for the period 1976-2004. Treatment schedules included oral cyclophosphamide (2-3 mg/kg) with prednisone 0.5-1 mg/kg (maximum 60 mg) only (n=90); prednisone on alternate days with methylprednisolone (30 mg/kg, maximum 1 g) and oral cyclophosphamide (n=117); oral prednisone on alternate days, three doses of intravenous methylprednisolone on alternate days and monthly doses of intravenous cyclophosphamide (500-750 mg m(-2) dose(-1)x7 doses monthly) (n=10); or cyclosporine 5 mg kg(-1) day(-1) adjusted to a trough level of 150-200 mg/ml (n=6). We compared the clinical and biochemical characteristics and outcome using different forms of therapies. A total of 183 (82.1%) underwent biopsy; 84 (45.9%) were Indian and 99 (54.1%) were black. Sixty-six (36.1%) had minimal change NS, 66 (36.1%) had focal segmental glomerulosclerosis (FSGS), 15 (8.2%) had a proliferative form of NS, and 36 (19.7%) had other forms of NS. Of the 84 Indian children biopsied, 58 (69.0%) were in complete remission, including 29 of 40 (72.5%) treated with oral cyclophosphamide and prednisone only. Of the 99 black children who were biopsied, 20 (20.2%) achieved complete remission; none of those treated with oral cyclophosphamide and prednisone only achieved complete remission. Of the 40 Indian children who were not biopsied who received only oral prednisone and cyclophosphamide, 32 (80%) achieved complete remission. This study shows Indian children with SRNS respond better to treatment than black children (69.0 vs. 20.2%). Since 80% of Indian children with SRNS responded to a trial of oral cyclophosphamide and prednisone, we propose the use of oral cyclophosphamide therapy in non-black children before embarking on renal biopsy.

Adolescent↗

PubMed1999

Intravenous cyclophosphamide pulse therapy for the treatment of lung disease associated with scleroderma.

Until recently, renal crisis was the most significant cause of morbidity and mortality in patients with scleroderma (SSc). Nowadays, following the introduction of angiotensin-converting enzyme inhibitors used in renovascular hypertension, pulmonary fibrosis and pulmonary hypertension have become the most common causes of death in SSc. Consequently, the early diagnosis and treatment of pulmonary fibrosis is essential to improve morbidity and mortality in SSc patients. The aim of this study was to investigate the effect of intravenous cyclophosphamide pulse therapy in patients with SSc and evidence of active alveolitis assessed on a high resolution computed tomographic (HRCT) scan, and to compare the effect of cyclophosphamide pulse therapy with oral therapy. Sixteen consecutive patients with SSc were allocated alternately to the two treatment groups. Eight patients were treated with monthly cyclophosphamide pulse therapy (750 mg/ m2) for 12 months; the other eight patients were treated with oral cyclophosphamide (2-2.5 mg/kg/day) for the same period. All patients received concurrently prednisone (10 mg/day). Pulmonary function tests and HRCT scans were performed before therapy and at 6 and 12 months. In the oral cyclophosphamide group, three patients with a grade I pattern showed regression of disease extent. In the other five patients (one with grade II and four with grade III) the pattern and extent of disease remained stable during the study. No statistical differences were found in forced expiratory volume in 1 s, forced vital capacity and total lung capacity during the study period. The diffusing capacity for carbon monoxide increased significantly between baseline and 12 months (p = 0.043). In the cyclophosphamide pulse therapy group, seven patients with a grade I pattern showed regression of disease extent at 6 months (p = 0.018) and 12 months (p = 0.012). One patient with grade III remained stable during the study. In both groups the regression of the extent of disease estimated on HRCT was due to a decrease in the ground glass appearance. The extent of the reticular appearance remained stable throughout the study. Our results indicate that cyclophosphamide pulse therapy is effective in suppressing active alveolitis (ground glass appearance). Although in this study it is not possible to compare pulse therapy with oral therapy because of the different pattern seen on HRCT between the two groups, it seems that oral therapy is also effective in suppressing active alveolitis. Neither regimen improved pulmonary involvement when the reticular appearance predominated over the ground glass appearance on HRCT. It is concluded that either pulse or oral cyclophosphamide therapy may improve the outcome of SSc patients.

Adult↗

PubMed1986

Cyclophosphamide in the seminal fluid of treated males: transmission to females by mating and effect on pregnancy outcome.

Cyclophosphamide is an anticancer and immunosuppressant drug administered to men of reproductive age. In the present study the ability of cyclophosphamide and/or its metabolites to enter secretions of the male reproductive tract, to be transmitted to the female partner upon mating, and to alter progeny outcome was assessed. [14C]Cyclophosphamide was given intravenously to adult male Sprague-Dawley rats; radiolabel (greater than 96% cyclophosphamide) was first found in seminal vesicle fluid within 10 min and equilibrated with plasma radioactivity within 30 min. Furthermore, radiolabel from cyclophosphamide given to the male was transmitted to the female upon mating up to 5 hr post-drug treatment. To study possible consequences of paternal treatment with cyclophosphamide on pregnancy outcome, male rats were administered a single dose of cyclophosphamide, 10, 30, or 100 mg/kg, or saline immediately prior to cohabitation with females in proestrus. There was no effect on the number of pregnant females per sperm-positive females but there was a significant decrease in the number of implantations per pregnant female per male and in the number of live fetuses per pregnant female per male. There was a twofold increase in preimplantation loss. There was no increase in postimplantation loss or number of abnormal fetuses. These results demonstrate that cyclophosphamide not only penetrates the male reproductive tract but that it can be transmitted to the female partner and can affect progeny outcome.

Animals↗

PubMed1986

Sodium 2-mercaptoethane sulfonate protection against cyclophosphamide-induced teratogenicity in rats.

Certain deleterious effects of cyclophosphamide, for example urotoxicity, can be prevented by the administration of thiol compounds such as 2-mercaptoethane sulfonate (MESNA) without altering the therapeutic efficacy of cyclophosphamide. To evaluate the effect of MESNA on the teratogenicity of cyclophosphamide, pregnant Sprague-Dawley rats were divided into nine treatment groups. Individual groups were administered 0.9% NaCl or cyclophosphamide (10 or 15 mg/kg) alone or in combination with MESNA at one of two doses (5 or 30 mg/kg) on Day 13 of gestation. The fetuses were examined for malformations on Day 20 of gestation. Cyclophosphamide alone produced malformations in 50% (10 mg/kg) or 100% (15 mg/kg) of the fetuses. The abnormalities observed were hydrocephaly, hind- and forelimb defects, open eyes, cleft palate, edema, micrognathia, omphalocele, and various skeletal defects. MESNA alone did not induce a significant number of fetal malformations compared to control. The low dose of MESNA had no significant effect on the total incidence of external malformations produced by either dose of cyclophosphamide. The high dose of MESNA significantly reduced the total number of externally abnormal fetuses and fetuses with skeletal defects produced by both 10 and 15 mg/kg of cyclophosphamide. This protection, although statistically significant (p less than or equal to 0.05), is probably not extensive enough for MESNA to be considered effective in protecting pregnant women from the teratogenic effects of cyclophosphamide chemotherapy.

Animals↗