SEARCH · PubMed Health

Results for “CYCLOPHOSPHAMIDE”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 487 records · Page 27Linked to original sources

PubMed2001

Acute rhabdomyolysis following administration of high-dose cyclophosphamide: case report.

Rhabdomyolysis is an unusual complication of hematopoietic stem cell transplantation (HSCT). Cyclophosphamide has been one of the key drugs in the most common preparative regimen for HSCT. We present here a rare case of acute rhabdomyolysis following administration of high-dose cyclophosphamide. A 47-year-old woman with adult T-cell leukemia in remission was treated with high-dose cyclophosphamide as a preparative regimen for allogeneic bone marrow transplantation. Nineteen hours later, general convulsions and acidosis suddenly occurred. Levels of serum creatine kinase (skeletal muscle type), myoglobin, and aldolase were markedly elevated to 32870 IU/l, 640 ng/ml, and 240.3 IU/l, respectively. Rhabdomyolysis caused by high-dose cyclophosphamide was diagnosed, and the preparative chemotherapy was discontinued. Subsequently, her muscular signs and symptoms improved, and the results of laboratory examinations returned to normal after 2 weeks. She had previously been treated with conventional doses of cyclophosphamide, doxorubicin, vincristine, and prednisolone without evidence of rhabdomyolysis. Acute rhabdomyolysis may be an adverse effect specific to high-dose cyclophosphamide therapy.

Acute Disease↗

PubMed1996

Inhibition of bacterial translocation from the gastrointestinal tract of mice injected with cyclophosphamide.

Effects of intraperitoneal injection of cyclophosphamide, an immunosuppressant, on the degree of bacterial translocation and morphological changes of Peyer's patches (PP) in the intestine were investigated with antibiotic-decontaminated SPF mice and germfree mice monoassociated with Escherichia coli C25. It has been reported that treatment with cyclophosphamide induces bacterial translocation. Cyclophosphamide treatment in this study, however, significantly decreased E. coli C25 translocation from the gastrointestinal tract to the mesenteric lymph nodes (MLN), although the numbers of lymphoid cells, especially B cells, in the PP, MLN, and spleen were remarkably reduced. Four injections of cyclophosphamide at a dose of 100 mg/kg inhibited bacterial translocation more than one injection at a dose of 200 mg/kg in SPF mice. Germfree mice, however, treated with one dose of 200 mg/kg showed the same inhibition of bacterial translocation as those given 100 mg/kg four times. In cyclophosphamide-treated mice, lymph follicles in the PP were obviously smaller than those in control mice, M-cells were similar in appearance to absorption epithelial cells except for short microvilli, and immune cells among the M-cells had disappeared. These data suggested that inhibition of bacterial translocation in mice treated with cyclophosphamide may be the result of morphological and physiological changes of epithelial cells in the gastrointestinal tract, especially M-cells, as a point of entry of invading bacteria, independent of the changes in immunological function.

Animals↗

PubMed2003

The efficacy of oral cyclophosphamide plus prednisolone in early diffuse systemic sclerosis.

Pharmacological treatment of diffuse systemic sclerosis (SSc) directed at the tissue fibrosis has generally been ineffective. Many immunosuppressive drugs have been tried as therapy for SSc, regardless of the disease subtype and/or stage. The aim of this study was to show the efficacy and the toxicity of oral cyclophosphamide and prednisolone therapy on the prevention of fibrosis-based tissue damage in the early stages of the diffuse SSc. Twenty-seven patients with early diffuse SSc were treated with oral cyclophosphamide (1-2 mg/kg/day) plus oral prednisolone (40 mg/every other day) between the years 1995 and 1998. The results regarding the efficacy and toxicity of cyclophosphamide were compared with those of 22 early SSc patients who had been treated with oral D-penicillamine between 1992 and 1995. All the patients were evaluated using clinical and laboratory parameters every 6 months for 2 years. There was a significant improvement on the skin score, maximal oral opening, flexion index, predicted forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLCO) in the cyclophosphamide group. The decrease in skin score in the cyclophosphamide group started earlier than in the D-penicillamine group. No life-threatening or irreversible adverse reaction was observed. This open study supports the use of oral cyclophosphamide plus prednisolone therapy to prevent fibrosis and its complications in the early stages of diffuse SSc.

Administration, Oral↗

PubMed2004

Cyclophosphamide is contraindicated in patients with a history of transitional cell carcinoma.

Cyclophosphamide is a urotoxic agent that increases the incidence of malignant neoplasms of the urinary tract. The aim of this study was to evaluate the long-term impact of cyclophosphamide on patients with a history of superficial bladder cancer. Between July 1986 and January 1988, 58 consecutive patients with primary superficial transitional cell carcinoma of the bladder were included in this study. All patients had a transurethral R0 resection. Then 6 weekly intravesical instillations of 120 mg bacillus Calmette-Guérin (BCG) were performed. Until June 1987, 22 consecutive patients (group A) received an additional intravenous application of 700 mg/m(2) cyclophosphamide prior to the BCG immunotherapy, while from July 1987 36 patients were treated without cyclophosphamide. Survival was calculated using the Kaplan-Meier method and comparison of survival using the log rank test. Tumor staging, grading, and size were equally distributed in both groups. No significant difference could be observed regarding the 10-year overall survival rate (group A: 59%, group B: 58%), the 10-year tumor-specific survival rate (89 vs 94%), and the 10-year progression-free survival rate (85 vs 97%). There was a statistically significant deterioration of the 10-year recurrence-free survival rate in the cyclophosphamide group (44 vs 70%, log rank test: p < 0.05). Whereas there were no recurrences in the upper urinary tract among the patients of group B, 2 of the 22 patients from group A developed cancer of the renal pelvis. In patients with a history of superficial bladder cancer, a single dose of cyclophosphamide poses a significantly increased risk of tumor recurrence in the lower and in the upper urinary tract as well.

Administration, Intravesical↗

PubMed2006

Immunohistochemical study of monocyte chemoattractant protein-1 in the pancreas of NOD mice following cyclophosphamide administration and during spontaneous diabetes.

In type 1 diabetes mellitus (T1DM), the processes which control the recruitment of immune cells into pancreatic islets are poorly defined. Complex interactions involving adhesion molecules, chemokines and chemokine receptors may facilitate this process. The chemokine, monocyte chemoattractant protein-1 (MCP-1), previously shown to be important in leukocyte trafficking in other disease systems, may be a key participant in the early influx of blood-borne immune cells into islets during T1DM. In the non-obese diabetic (NOD) mouse, the expression of MCP-1 protein has not been demonstrated. We employed dual-label immunohistochemistry to examine the intra-islet expression, distribution and cellular source of MCP-1 in the NOD mouse following cyclophosphamide administration. NOD mice were treated with cyclophosphamide at day 72-73 and MCP-1 expression studied at days 0, 4, 7, 11 and 14 after treatment and comparisons were made between age-matched NOD mice treated with diluent and non-diabetes-prone CD-1 mice. Pancreatic expression of MCP-1 was also examined in NOD mice at various stages of spontaneous diabetes. In the cyclophosphamide group at day 0, MCP-1 immunolabelling was present in selective peri-islet macrophages but declined at day 4. It increased slightly at day 7 but was more marked from day 11, irrespective of diabetes development. The pattern of MCP-1 expression in macrophages was different over time in both the cyclophosphamide and control groups. In the cyclophosphamide group, there was a change over time with an increase at day 11. In the control group, there was little evidence of change over time. There was no significant difference in the mean percentage of MCP-1 positive macrophages between the cyclophosphamide-treated diabetic and non-diabetic mice. During spontaneous diabetes in the NOD mouse, only a few peri-islet MCP-1 cells appeared at day 45. These became more numerous from day 65 but were absent at diabetes onset. We speculate that a proportion of early islet-infiltrating macrophages which express MCP-1 may attract additional lymphocytes and macrophages into the early inflamed islets and intensify the process of insulitis.

Animals↗

PubMed1986

Induction of sister chromatid exchanges in human and rat hepatoma cell lines by cyclophosphamide and phosphoramide mustard and the effects of cytochrome P-450 inhibitors.

The activity of the cytochrome P-450-associated metabolic pathway in human (HepG2) and rat (H4-II-E) hepatoma cells was examined. The genotoxic activities of cyclophosphamide and its direct acting metabolite, phosphoramide mustard, were studied in the hepatoma cells as cyclophosphamide is known to be metabolized by phenobarbital-inducible cytochrome P-450-associated metabolic activity. HepG2 and H4-II-E demonstrated the capacity to activate cyclophosphamide to forms capable of inducing sister chromatid exchanges in concentration-dependent fashion. Phosphoramide mustard induced a similar pattern of sister chromatid exchanges at concentrations three orders of magnitude lower than cyclophosphamide. The cytochrome P-450-associated enzyme inhibitors, SKF-525A and metyrapone, were found to reduce the level of cyclophosphamide-induced sister chromatid exchanges in HepG2 and H4-II-E, suggesting that cyclophosphamide was activated by this pathway in both hepatoma lines. Direct evidence for the presence of mRNA transcript coding for a phenobarbital-inducible cytochrome P-450 was demonstrated in HepG2 cells by Northern blot analysis. Comparison of genotoxic responses in human and rat hepatoma cells may allow for an evaluation of responses by different species to potentially mutagenic chemicals.

Animals↗

PubMed1975

The effect of plasma on the reaction of cyclophosphamide with 4(-p-nitrobenzyl)-pyridine.

Cyclophosphamide is not structurally modified by blood plasma and may be recovered quantitatively from it. The apparent loss of alkylating ability of cyclophosphamide, as measured by its ability to react with 4-(p-nitrobenzyl)-pyridine (NBP), following treatement with plasma is not, as has been reported, due to metabolism of the drug but rather to an inhibition of the colorimetric reaction by a constituent of the plasma. This inhibition is strongly pH dependent, reaching 100% when the pH of the solution of cyclophosphamide in plasma is above 8, and falling to less than 20% when the pH is below 6, but extraction with chloroform at pH 7 separates cyclophosphamide from the inhibitor. Although the nature of the inhibitor has not been elucidated, its presence in plasma is of great importance in the quantitative determination of cyclophosphamide, and may also be of significance in the biological effects of cyclophosphamide and other alkylating agents in vivo.

Alkylating Agents↗

PubMed1985

Pulmonary toxicity of cyclophosphamide: a 1-year study.

The development of cyclophosphamide-induced pulmonary lesions over a 1-year period was studied in mice. Male BALB/c mice received a single intraperitoneal injection of 100 mg/kg of cyclophosphamide. Within 3 weeks there were scattered foci of intraalveolar foamy macrophages. With time, these foci increased in size and, 1 year later, occupied large areas in all lung lobes. There was also diffuse interstitial fibrosis. Chemical determination done 3, 12, 24, and 52 weeks after cyclophosphamide showed that lungs of animals treated with cyclophosphamide had significantly more hydroxyproline per lung than controls. One year after cyclophosphamide pressure-volume curves measured in vivo were shifted down and to the right and total lung volumes were decreased. A single injection of cyclophosphamide produced an irreversible and progressive pulmonary lesion.

Animals↗

PubMed1990

Modulation of the control of mutagenic metabolites derived from cyclophosphamide and ifosfamide by stimulation of protein kinase A.

The phosphorylation of the 2 major phenobarbital-inducible cytochrome P450 isoenzymes IIB1 and IIB2 was increased in intact hepatocytes by the action of the membrane-permeating cAMP derivative N6,O2'-dibutyryl-cAMP. Under these conditions cyclophosphamide and ifosfamide (which are known to be activated by cytochrome P450 IIB1) were investigated for mutagenicity in Salmonella typhimurium TA1535 and TA100 and for cytotoxicity in TA1535. Cyclophosphamide and ifosfamide were transformed to mutagenic and cytotoxic metabolites by the hepatocytes. The activation of both drugs to mutagens was markedly reduced after pretreatment of the hepatocytes with the membrane-permeating cAMP derivative N6,O2'-dibutyryl-cAMP. Cyclophosphamide and ifosfamide activation were reduced to 51% and 38% of unstimulated controls respectively, when hepatocytes were incubated for 1 h with N6,O2'-dibutyryl-cAMP in the presence of the phosphodiesterase inhibitor theophylline, and Salmonella typhimurium TA1535 was used. A marked reduction in mutagenicity of cyclophosphamide (35% compared with unstimulated controls) was also observed under different experimental conditions, namely after pretreatment of the hepatocytes with N6,O2'-dibutyryl-cAMP for 1.5 h without theophylline and using Salmonella typhimurium TA100 as target strain. Continued presence of the cytochrome P450 IIB1 and P450 IIB2 inducer phenobarbital in the stimulation medium increased the mutagenicity of cyclophosphamide and led to an even more marked reduction of mutagenicity by pretreatment of the hepatocytes with N6,O2'-dibutyryl-cAMP and theophylline. In order to investigate whether the observed changes were metabolism-related, the ifosfamide metabolite ifosfamide mustard which does not require metabolic activation by cytochrome P450 was studied under the same conditions. Its mutagenicity was indistinguishable after incubation with N6,O2'-dibutyryl-cAMP-treated or with unstimulated hepatocytes. Also the metabolic formation of cytotoxic metabolites from cyclophosphamide and ifosfamide but not that of ifosfamide mustard was markedly decreased by pretreatment of the hepatocytes with N6,O2'-dibutyryl-cAMP and theophylline. Thus the stimulation of protein kinase A in intact cells has important consequences for the control of genotoxic and cytotoxic metabolites and represents a fast and short-term regulation of it.

Animals↗

PubMed1986

Phase II trial of misonidazole (MISO) and cyclophosphamide (CYC) in metastatic renal cell carcinoma.

In animal models pre-treatment with misonidazole, a hypoxic cell radiosensitizer, enhances the antineoplastic effects of alkylating agent chemotherapy. Laboratory data suggest that hypoxic tumor cells may be more resistant to chemotherapy because of suboptimal drug delivery, reduced rates of cell division, or because hypoxia confers relative drug resistance. The therapeutic potential depends on the tumor type, doses of radiosensitizer and alkylating agent, the time interval between drug administration, and the ratio of sensitization of normal and malignant tissues. A Phase II trial of misonidazole and cyclophosphamide was initiated by the Eastern Cooperative Oncology Group to determine the response rate and toxicity in patients with metastatic renal cell cancer. Patients received 5 gm/m2 of misonidazole intravenously two hr before 1200 mg/m2 of cyclophosphamide every 3 wk. Patients with prior chemotherapy or radiotherapy received 1000 mg/m2 of cyclophosphamide. Misonidazole was discontinued after a total dose of 15 gm/m2. The median total misonidazole dose was 23.5 gm (range 4.5-34.5 gm). The median number of cyclophosphamide cycles was 2 (range 1-12). Of the 30 patients evaluable for response, only one patient had an objective partial response. Twenty-nine patients had stable or progressive disease. One patient remains on cyclophosphamide after 9 mo. Estimated median survival is 4.8 mo. There have been no lethal toxicities; however, 9 patients (25%) experienced life-threatening leukopenia and an additional 42% experienced severe hematologic toxicity. Eight patients had WBC less than 1000 on days 7-14 of cycle 1. Thrombocytopenia and grade 3 anemia occurred in 1 and 2 patients, respectively. Moderate or severe nausea and vomiting occurred in 47% and 19% of patients, respectively. Only 3 patients experienced severe neurotoxicity. Four additional patients had moderate neurotoxicity. In summary, misonidazole in this dosing schedule does not enhance the antitumor activity of cyclophosphamide in renal cell carcinoma.

Carcinoma, Renal Cell↗

PubMed2004

Oral low-dose cyclophosphamide in metastatic hormone refractory prostate cancer (MHRPC).

The chemotherapeutic approach to hormone-refractory metastatic prostate cancer (MHRPC) for a long time included only estramustine. Then, attempts have been made with other various agents as cyclophosphamide, vinblastine, etoposide, taxanes and carboplatinum. Although the new drugs and combinations have increased the response rate of MHRPC, they have had no impact on the natural history of MHRPC, which is about 1 year as median time of survival. After an occasional observation of prolonged response in a patient with MHRPC treated with a very well tolerated oral low-dose of cyclophosphamide, from February 1996 to October 2002, seven more patients with MHRPC and progressive disease were consecutively recruited. Response to treatment was evaluated by conventional radiological procedures and/or serial serum PSA measurements. The decline of PSA value was considered to assess the response consistent with the response guidelines from the prostate specific antigen-working group. All eight studied patients continuously received oral low dose cyclophosphamide until progression or the occurrence of significant toxicity. So far three patients (37.5%) progressed (PD), two (25%) showed PR and the three remaining SD. Response rate was 25%, and clinical benefit occurred in 62.5% of the studied patients. In the five patients with clinical benefit on cyclophosphamide median duration of clinical benefit, PR and SD were 9, 24+ and 8 months, respectively. In these five patients median overall survival times from cyclophosphamide and from the first regimen of chemotherapy were 17 and 33+ months respectively, while in the three patients with PD they were 4 and 13 months. The same interval times in patients with > or =50% decline of serum PSA were 29 and 50.5 months, while in those with <50% decline of the same marker, they were 13 and 32 months, respectively. Grade 2 or 3 neutropenia were observed in all the studied patients. In four (50%) of them pulmonary and urinary infections that were easily cured by the common antibiotics occurred. These data suggest that the metronomic use of cyclophosphamide, given alone, has similar or higher activity with lower toxicity than when administered with other active drugs. So it can be an useful option before or after the use of other single or combined potentially active chemotherapeutic agents.

Administration, Oral↗

PubMed2004

Cardiac toxicity observed in association with high-dose cyclophosphamide-based chemotherapy for metastatic breast cancer.

INTRODUCTION: Cyclophosphamide is an alkylating agent given frequently as a component of many conditioning regimens. In high doses, its nonhematological dose-limiting toxicity is cardiomyopathy. STUDY DESIGN: We combined paclitaxel, melphalan and high-dose cyclophosphamide, thiotepa, and carboplatin in a triple sequential high-dose regimen for patients with metastatic breast cancer. Analysis was performed on 61 women with chemotherapy-responsive metastatic breast cancer receiving 96-h infusional cyclophosphamide as part of a triple sequential high-dose regimen to assess association between presence of peritransplant congestive heart failure (CHF) and the following pretreatment characteristics: presence of electrocardiogram (EKG) abnormalities, age, hypertension, prior cardiac history, smoking, diabetes mellitus, prior use of anthracyclines, and left-sided chest irradiation. RESULTS: Six of 61 women (10%) developed clinically reversible grade 3 CHF following infusional cyclophosphamide with a median percent decline in ejection fraction of 31%. Incidence of transient cyclophosphamide-related cardiac toxicity (10%) is comparable to previous recorded literature. Older age was significantly correlated with the CHF development; with median ages for the entire group and for patients developing CHF of 45 and 59, respectively. No association was found with other pretreatment characteristics. CONCLUSIONS: As a result of these findings, oncologists should carefully monitor fluid balance in older patients. Routine EKG monitoring during infusional cyclophosphamide did not predict CHF development.

Adult↗

PubMed2006

Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced hyperlipidemic cardiomyopathy.

Cyclophosphamide is a potent alkylating agent used in cancer chemotherapy and immunosuppression. The present study is aimed at evaluating the role of a potent antioxidant lipoic acid in cyclophosphamide induced hyperlipidemic cardiomyopathy. Adult male Wistar rats were divided into four treatment groups. Two groups received single intraperitoneal injection of cyclophosphamide (200 mg/kg body weight) to induce cardiotoxicity, one of these groups received lipoic acid treatment (25 mg/kg body weight, orally for 10 days). A vehicle treated control group and a lipoic acid drug control were also included. Cyclophosphamide administration resulted in abnormal elevation of serum lipids. Similarly in the cardiac tissue, the levels of free cholesterol, esterified cholesterol, triglycerides were increased significantly (P<0.05) while the levels of phospholipids and free fatty acids were reduced significantly unlike serum (P<0.05). Serum Low Density Lipoprotein (LDL) and Very Low Density Lipoprotein (VLDL) cholesterol increased significantly (P<0.05) while High Density Lipoprotein (HDL) cholesterol (P<0.05) decreased significantly when compared to controls. These changes corroborated with the abnormal distortion in the activities of lipid metabolizing enzymes in cyclophosphamide treated group. Supplementation of lipoic acid reverted these abnormalities in the lipid levels and activities of lipid metabolizing enzymes to near normalcy after cyclophosphamide administration.

Animals↗

PubMed2004

Preliminary analysis of a trial of pulse cyclophosphamide in IFN-beta-resistant active MS.

This was a randomized, single-blind, parallel-group, multicenter trial in MS patients with a history of active disease during IFN-beta treatment. Patients were randomized to either cyclophosphamide 800 mg/m2 plus methylprednisolone 1 g IV (CY/MP) or methylprednisolone (MP) once monthly for 6 months then followed for an additional 18 months. All patients received IFN-beta1a for the 24-month study period. The primary endpoint was mean change from baseline in the number of gadolinium-enhancing (Gd+) lesions. Secondary endpoints included the percentage of patients with Gd+ lesions, change in T2 lesion burden, change in brain parenchymal fraction (BPF), time to treatment failure, and cumulative probability of relapse. Safety was assessed by the incidence of adverse events and the results of blood and urine testing. A higher number of patients completed the study in the pulse cyclophosphamide group because approximately half as many of these patients became treatment failures (26% vs. 52%, p = 0.03). During the infusion phase, the mean number of Gd+ lesions declined 70-80% from baseline in the CY group vs. a small increase in MP (p = 0.02 and 0.04 at 3 and 6 months). We conclude that pulse cyclophosphamide appears to be well tolerated in combination with IFN-beta1a. Pulse cyclophosphamide decreases the number of Gd+ lesions in patients with active disease on IFN-beta compared to pulse methylprednisolone alone. Six doses of pulse cyclophosphamide in combination with IFN-beta1a both prevent and delay clinical disease activity in patients with previously active disease on IFN-beta alone. Pulse cyclophosphamide is a therapeutic option as rescue therapy for patients thought to be interferon non-responders.

Adult↗

PubMed1976

Gonadal function, testicular histology, and meiosis following cyclophosphamide therapy in patients with nephrotic syndrome.

Gonadal function, histology, and meiosis were studied in patients after puberty who had received cyclophosphamide in the treatment of nephrotic syndrome. Four males with minimal lesion nephrotic syndrome received cyclophosphamide, 2 to 4 mg/kg/24 hr, during periods ranging from 49 to 60 days and had normal semen at 15 3/12 to 22 3/12 years of age. Four males who received cyclophosphamide, 2 to 5 mg/kg/24 hr, during 89 to 489 days were azoospermic at 15 6/12 to 21 11/12 years of age. Plasma testosterone levels were normal in both groups. LH and FSH levels were elevated in the azoospermicgroup. Light and electron microscopy and meiotic analysis of testicular tissue were normal in two normospermic patients tested. Germinal cells were absent but Leydig and Sertoli cells were present in three azoospermic patients tested. No neoplasia was observed. Two preadolescent and two postadolescent males received 64 to 129 mg/kg of cyclophosphamide during 14 to 45 days and have since fathered normal children. One preadolescent female received 182 mg/kg of cyclophosphamide during 49 days and later bore a normal child. Two preadolescent females who died of complications of their nephrotic syndrome during childhood after courses of cyclophosphamide had normal preadolescent ovaries.

Adolescent↗

PubMed1990

The use of prostaglandin F2 alpha for the prophylaxis of cyclophosphamide induced cystitis in rats.

It is well-established that cystitis is a significant cause of morbidity after cyclophosphamide administration in clinical populations. We induced hemorrhagic cystitis in rats using cyclophosphamide and compared controls to those pretreated with prostaglandin F2 alpha. Rats were then evaluated for differences in bladder weights, gross edema, gross bleeding, and histologic changes. The weights of the bladders which had been treated with cyclophosphamide were 94% greater than the controls. The weights of the bladders which were pretreated with prostaglandin F2 alpha before cyclophosphamide were only 19% greater than controls. Significant differences were found between cyclophosphamide controls and prostaglandin F2 alpha pretreated groups for gross weight (p less than .0005), gross edema (p less than .0005), and histology (.0005 less than p less than .005). We conclude that prostaglandin F2 alpha may be helpful in preventing cyclophosphamide induced cystitis.

Animals↗

PubMed2000

Pulse intravenous cyclophosphamide therapy for dermatologic disorders.

Cyclophosphamide is a potent immunosuppressive agent that has an important role in the treatment of autoimmune, neoplastic, granulomatous, and neutrophilic disorders. Pulse intravenous cyclophosphamide has been shown to be efficacious for several dermatologic disorders, particularly pemphigus vulgaris, with a low incidence of toxicity reported. As reported earlier, studies performed on the use of pulse intravenous cyclophosphamide in the treatment of a variety of dermatology-related diseases strongly suggest that the toxicities frequently noted with the use of oral cyclophosphamide therapy may be significantly less common with pulse intravenous administration of cyclophosphamide. The short follow-up period of patients treated with this modality so far, however, requires constant vigilance for the development of side effects, particularly secondary malignancy. At this time, pulse intravenous cyclophosphamide is a promising treatment modality with an acceptable risk profile for moderate-to-severe dermatologic diseases recalcitrant to standard therapy. Prospective comparative trials are needed to assess further the efficacy and toxicity of this therapy.

Antineoplastic Agents, Alkylating↗

PubMed2000

Paternal exposure to cyclophosphamide induces DNA damage and alters the expression of DNA repair genes in the rat preimplantation embryo.

Chronic low dose treatment of male rats with cyclophosphamide, an anticancer alkylating agent, damages male germ cells, resulting in greater than 80% peri-implantation progeny loss. Little transcription or repair takes place in the DNA of post-meiotic male germ cells. The spermatozoal genome regains its transcriptional capacity in the fertilized oocyte. We hypothesized that as a consequence of exposure of male rats to cyclophosphamide DNA damage to the male genome is transmitted to the conceptus; furthermore, this damage leads to alterations in the expression profiles of DNA repair genes during preimplantation development. Male rats were treated with either saline or cyclophosphamide (6mg/kg/day, 4-6 weeks) and mated to control females; 1-8 cell stage embryos were collected. The alkaline comet assay was used to assess DNA damage in 1-cell embryos. A significantly higher percentage (68%) of the embryos fertilized by cyclophosphamide-exposed spermatozoa displayed a comet indicative of DNA damage, compared to those sired by control males (18%). The in situ transcription/antisense RNA approach was used to determine if DNA damage alters the expression of DNA repair genes in early embryos. Dramatic increases in the transcripts for selected members of the nucleotide excision repair family (XPC, XPE and PCNA), mismatch repair family (PMS1), and recombination repair family (RAD50) were found in 1-cell stage embryos sired by cyclophosphamide-treated males compared to controls, while decreases in the expression of base excision repair family members (UNG1, UNG2, and XRCC1) and in recombination repair transcripts (RAD54) were observed. By the 8-cell stage, transcripts for specific members of the nucleotide excision repair family (XPC) and mismatch repair family (MSH2, PMS2) were elevated greatly in control embryos compared to embryos sired by drug-treated males; in contrast, transcripts for other members of the nucleotide excision repair family (XPE, PCNA), as well as some of the base excision repair family (UNG1), were elevated in embryos sired by drug-treated males. Therefore, DNA damage incurred in spermatozoa, following cyclophosphamide exposure is associated with alterations in the expression profiles of DNA repair genes in preimplantation embryos as early as the 1-cell stage. Genotoxic stress may disturb the nuclear remodeling and reprogramming events that follow fertilization and precede zygotic genome activation.

Animals↗