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PubMedDate not supplied

Oral cyclophosphamide and oral hydroxyurea in the treatment of hormone refractory prostate cancer in rats.

Hormone refractory prostate cancer is a fatal disease and currently no standard cytotoxic chemotherapy exists for prostate cancer. The recent use of prostate specific antigen as an endpoint for clinical trial has resulted in the ability to test the activity of chemotherapy agents in a quick manner. The aim of this study was to investigate the activity of the oral combination of two familiar agents, cyclophosphamide and hydroxyurea, against hormone refractory prostate cancer. In vitro studies demonstrated that hydroxyurea was more active than cyclophosphamide against the anaplastic Dunning rat prostate cancer cell line, Mat-LyLu. In vivo experiments, however, demonstrated cyclophosphamide to be superior to hydroxyurea. The combination of both agents failed to enhance inhibition of subcutaneously implanted Mat-LyLu cells. A human trial of oral cyclophosphamide using prostate specific antigen as an intermediate endpoint may be warranted.

Adenocarcinoma↗

PubMed1994

Efficacy of rapamycin, RS-61443 and cyclophosphamide in the prolongation of survival of discordant pig to rabbit cardiac xenografts.

OBJECTIVE: To evaluate the efficacy of two new immunosuppressive drugs, RS-61443 and rapamycin, alone and in combination with cyclophosphamide in the prolongation of heterotopic cardiac xenograft survival in a discordant neonatal pig to rabbit model. DESIGN: Animals were randomly assigned to receive rapamycin intravenously (1.0 mg/kg/day) or RS-61443 subcutaneously (160 mg/kg/day) commencing five days before surgery until rejection occurred. Cyclophosphamide, 20 mg/kg/day, was administered from one day prior to surgery. Combination of the above drugs (rapamycin 1.0 mg/kg/day and RS-61443 80 mg/kg/day) with and without treatment with cyclophosphamide was also evaluated. Trough blood concentrations of rapamycin and mycophenolic acid as well as rabbit antiporcine endothelial cell antibodies (immunoglobulin [Ig]M) were measured every second day from the commencement of drug therapy. RESULTS: The mean +/- SD survival time in control animals was 7.98 +/- 13.85 h (n = 11), with the majority of animals (n = 6) rejecting their grafts in less than 1 h. Rapamycin (11.5 +/- 9.5 h), RS-61443 (9.8 +/- 6.1 h), cyclophosphamide (17.9 +/- 16 h) alone, or the three drugs in combination (16.6 +/- 9.1 h) resulted in a trend to increase graft survival, which did not reach significance. In contrast, rapamycin and RS-61443 in combination (24.3 +/- 11.9 h) significantly (P < 0.05) prolonged graft survival. No significant (P > 0.05) decrease in rabbit antiporcine endothelial cell IgM concentrations was observed in all drug-treated groups; however, considerable variation was noted within each group. No relationship was found between trough concentrations of rapamycin and mycophenolic acid and xenograft survival or with a decrease in antibody concentrations. CONCLUSION: The data suggest that treatment modalities, in addition to the above drugs, is required for prolonged survival in cardiac xenografts in the discordant animal model used here.

Animals↗

PubMed1994

Treatment of recurrent suprahyoid cervicofacial lymphangioma with intravenous cyclophosphamide.

PURPOSE: Surgical resection of cervicofacial cystic hygromas and lymphangiomas rarely effects complete reduction because of severe anatomic restrictions. PATIENTS AND METHODS: With prior knowledge of cyclophosphamide activity against lesions of this type, a formal trial of cyclophosphamide was initiated. RESULTS: Overall dose escalation therapy resulted in 50% reduction in mass without recurrence after cessation of therapy and with minimal and readily reversible toxicity. CONCLUSIONS: The favorable responses to cyclophosphamide in this study suggest that a prospective randomized trial should be initiated. Certainly, children who have airway and/or esophageal compromise who have failed surgical therapies should be considered for cyclophosphamide treatment.

Child↗

PubMed1994

Intermittent intravenous treatment of lupus nephritis with cyclophosphamide: a four-year experience with twenty-four patients.

BACKGROUND: Renal involvement in systemic lupus erythematosus commonly leads to renal failure and death. We conducted a study to evaluate the efficacy and side effects of intermittent intravenous treatment with cyclophosphamide of patients with lupus nephritis. METHODS: Twenty-four patients with lupus nephritis were recruited at Tri-Service General Hospital from 1988 to 1992. Cyclophosphamide was administered intravenously monthly for three months, and then every three months. 24-hour urinary protein, creatinine clearance, serum creatinine, blood urea nitrogen, C3 and C4 levels, serum albumin, hemoglobin, and dosage of prednisolone were recorded before each treatment. During treatment, the side effects were monitored. RESULTS: Two patients progressed to renal failure within one year and one patient after three years. Fifteen patients completed therapy for one year. Among these 15 patients, the levels of hemoglobin, serum albumin, and C3 significantly increased at six months, then became stable; the level of C4 increased at 12 months. In contrast, the dosage of prednisolone decreased significantly at six months. There was no significant difference of creatinine clearance, 24-hour urinary protein, serum creatinine, and blood urea nitrogen before and after treatment. The most common side effects were nausea and vomiting. No severe side effect necessitated discontinuing therapy with cyclophosphamide. CONCLUSIONS: Intermittent intravenous therapy in lupus nephritis with cyclophosphamide can significantly increase levels of hemoglobin, serum albumin, C3 and C4, and keep renal function stable. Poor response was found in a subset of patients. The side effects were mild in the present study.

Adult↗

PubMed1994

Immunosuppressive therapy with cyclophosphamide and prednisolone in severe idiopathic membranous nephropathy.

In idiopathic membranous nephropathy (IMN) immunosuppressive therapy should be reserved for patients with potential risk factors at baseline or who show a progressive course. Cyclophosphamide pulse therapy (CPT) in IMN is not yet widely tested. We carried out a trial of CPT combined with conventional treatment in a group of patients with IMN at a greater risk. The study group consisted of 36 nephrotic adult IMN patients (M, 26; F, 10) with various combinations of risk factors. Mean proteinuria was 11.3 g/day, 47% patients were hypertensive, 78% had tubular changes, and 36% had focal glomerulosclerosis. They were treated with CPT and/or conventional low-dose cyclophosphamide and prednisolone. Median duration of immunosuppression was 14 months and median total cumulative dose of cyclophosphamide 172 mg/kg body weight. At 6 months (6m) remission was achieved in 44% cases and at the 36th month in 73%. None of the patients developed moderate or severe renal failure. Side-effects were minimal. Multivariate analysis of baseline data and the changing course of the disease during therapy showed that tubular changes (P = 0.0025), creatinine clearance at baseline (P = 0.04) and at 6m (P = 0.02), and proteinuria at 6m (P < 0.0001) significantly influenced the therapeutic effect. We conclude that cyclophosphamide (including pulse) and prednisolone can bring significant remission and maintain renal function in IMN with potential risk factors.

Adult↗

PubMed1993

[Protective effect on ischemic depletion of nucleotide phosphates in heart, brain, and kidney by cyclophosphamide].

The levels of ATP, ADP, and AMP in heart, brain, and kidney suffering from 10-min ischemia after decapitation in rats were determined by a modified reverse-phase HPLC set with uv detection. The ischemic depletion of ATP was alleviated and the total amount of high energy phosphates was markedly reduced by the treatment of po cyclophosphamide 20 and 100 mg.kg-1 x 3 d. The protective effect on depleting the total amount of high energy phosphates which was better preserved than ATP in ischemic organs by cyclophosphamide was evidenced in a dose-related manner. Cyclophosphamide induced leukopenia in circulating blood. Two reasons for the anti-arrhythmic effect of cyclophosphamide are suggested: 1) the depletion of leukocyte reduced the plugging effect of neutrophil in myocardial capillaries; 2) blocking the KATP channel by elevating ATP level in myocardium.

Adenosine Triphosphate↗

PubMed1993

Cyclophosphamide versus ifosfamide: a randomized phase II trial in adult soft-tissue sarcomas. The European Organization for Research and Treatment of Cancer [EORTC], Soft Tissue and Bone Sarcoma Group.

Ifosfamide (5 g/m2) was compared with its parent analogue cyclophosphamide (1.5 g/m2) in a randomized phase II study. Both drugs were given by 24-h intravenous (i.v.) infusion every 3 weeks along with i.v. bolus infusions of mesna (400 mg/m2), which was given every 4 h for nine administrations. Eligibility criteria included an age of 15-75 years, biopsy-proven advanced metastatic soft-tissue sarcoma, and a World Health Organization performance status of 0-2. Exclusion criteria were prior treatment with classic alkylating agents, a creatinine level of > 150 mumol/l, a bilirubin level of > 20 mumol/l, a leukocyte cell count of < 3.5 x 10(9)/l, and a platelet count of < 100 x 10(9)/l. A total of 171 patients were entered, 24 of whom were ineligible and 12, inevaluable, leaving 135 patients evaluable. In all, 67 patients were treated with cyclophosphamide, and the overall response rate was 7.5%. All responders to cyclophosphamide were patients who had not received prior chemotherapy (13% of 38 patients). Another 68 patients were given ifosfamide, 18% of whom responded to treatment. Of the 28 ifosfamide-treated patients who had received prior chemotherapy, 7% were responders. The response rate for the remaining 40 patients was 25%. The higher overall response rate (P = 0.13) obtained with less myelosuppression in ifosfamide-treated patients suggests that this agent may have advantages over cyclophosphamide in combination therapy.

Adolescent↗

PubMed1993

[Dexamethasone-cyclophosphamide pulse therapy in bullous autoimmune dermatoses].

The problem in the treatment of bullous autoimmune dermatoses with long-term corticosteroids is that the high doses cause side-effects. An alternative form of therapy with high-dose dexamethasone-cyclophosphamide pulses was used to treat 20 patients between 33 and 86 years: 7 patients had bullous pemphigoid, 6 pemphigus vulgaris, 5 pemphigus foliaceus, and 2 cicatricial pemphigoid. On each of days 1-3 100 mg dexamethasone was administered i.v. and on day 1, 500 mg cyclophosphamide i.v. In the therapy interval between the pulses 50 mg cyclophosphamide per day. Initially the pulses were repeated every 2 weeks and later at 10-week intervals. After 6 months of this regimen 13 patients were symptom-free, 4 had improved, and 3 showed no change. The efficacy of treatment was equal in newly diagnosed and previously treated cases. (Side-effects were leucopenia (n = 3), myalgia and arthralgia (n = 2), taste disturbance (n = 2), diffuse hair loss (n = 2), thrombophlebitis (n = 1), herpes zoster (n = 1) and a delayed-type hypersensitivity reaction to mesna. Owing to the rather short follow-up, no conclusions on long-term side-effects of this therapy are possible. However, dexamethasone-cyclophosphamide pulse therapy appears so far to be a good alternative to the standard continuous corticosteroid treatment.

Adult↗

PubMed1993

Respiratory failure in Wegener's granulomatosis: response to pulse intravenous methylprednisolone and cyclophosphamide.

We describe a patient with respiratory failure due to Wegener's granulomatosis (WG) who obtained a dramatic and sustained response to pulse intravenous methylprednisolone and cyclophosphamide. Discussion includes a review of the literature with respect to the relative merits of daily oral cyclophosphamide versus pulse intravenous cyclophosphamide in WG and other vasculitides. While the combination of daily oral steroids and daily oral cyclophosphamide dramatically improves the outcome of WG, this therapy is not without serious side effects. Pulse therapy may be equally as effective and may lessen the frequency of serious side effects.

Administration, Oral↗

PubMed1993

[Immunosuppressive effect of cyclophosphamide in experimental coagulase-negative staphylococcal infection].

BALB/c mice were given 200 mg/kg cyclophosphamide intraperitoneally. Three days later, mice were infected intraperitoneally with Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus saprophyticus at 4 inocula ranging between 2 x and 20 x 10(8) CFU/ml suspended in dextran microcarrier solution. Controls were treated only with bacteria. Lethality rates and organ persistence of cocci were significantly higher, and more peritoneal abscesses and adhesions developed in the mice pretreated with cyclophosphamide than in the untreated controls, regardless of the species of Staphylococcus injected. Splenomegaly was also more pronounced indicating a probably enhanced compensatory reactivity of the immune system liberated from suppression 13 days after the administration of cyclophosphamide. Our results show that cyclophosphamide treatment increases the susceptibility of mice to infection by coagulase-negative staphylococci and it is also responsible for a more severe course of the diseases provoked.

Animals↗

PubMed1995

[Pulse-dose cyclophosphamide therapy for steroid-refractory autoimmune neurological diseases].

Eight patients with neuroimmunological disorders refractory to conventional immunotherapies were given totally 17 courses of pulse-dose cyclophosphamide. The regimen consisted of 600 mg/m2 of intravenous cyclophosphamide at days 1,2,4,6 and 8 and infusion of 2,500-3,000 ml of fluids in order to avoid hemorrhagic cystitis. Some cases were followed by a monthly intravenous dose of cyclophosphamide as a booster treatment. As a result, all but one case of neuro-Behçet disease have shown neurological improvements. In particular, a complete remission was obtained in two cases of vasculitic neuropathy and a case of chronic inflammatory demyelinating polyneuropathy. The side effects, notably, granulocytopenia, alopecia, hemorrhagic cystitis and anorexia, are major problems. Granulocytopenia started 10 days after the first dose and the number of leucocytes was the lowest at day 15. However, the number steadily recovered thereafter without the use of granulocyte colony stimulating factor. There was no serious infections during the course. For neuroimmunological disorders, the pulse-dose cyclophosphamide therapy would serve a useful alternative when the conventional therapies are not efficacious or difficult to continue because of the adverse side effects.

Adult↗

PubMed1995

High-dose carboplatin, etoposide and cyclophosphamide with autologous bone marrow transplantation for the treatment of advanced malignancies: a phase I study.

Carboplatin is a platinum-derivative widely used in conditioning regimens with ABMT, particularly in combination with cyclophosphamide and etoposide, drugs which co-express synergism in vitro. The objective of this study was to determine the maximum tolerated dose (MTD) of this combination. Thirty-four patients with refractory lymphoid or solid tumors were treated in a dose-escalation study with continuous infusion carboplatin (1.2-2 g/m2) on days -7 to -4, etoposide (1.2-2.4 g/m2) on days -7 to -5 and cyclophosphamide (120 mg/kg) given in two dose schedules: (1) day -3, -2; (2) day -9, -8. Autologous bone marrow or peripheral blood stem cells were infused on day 0. Mucositis/enterocolitis was dose limiting. In addition, severe cardiac dysfunction occurred in schedule 1 but not in schedule 2. Renal dysfunction occurred in the setting of fungemia, respiratory failure and congestive heart failure, and did not correlate with carboplatin dose. Hepatic and pulmonary dysfunction were minimal. The MTD was etoposide 2.1 g/m2 and carboplatin 2.0 g/m2, in combination with cyclophosphamide (120 mg/kg) on schedule 2. Responses were seen in 16 of 19 patients with measurable disease. Seven patients are disease-free survivors 50-60+ months post-ABMT. This study defines the MTD of carboplatin when combined with etoposide and cyclophosphamide in patients with adequate renal function and suggests significant anti-tumor activity.

Adolescent↗

PubMed1977

Characterization and quantitative estimation of activated cyclophosphamide in blood and urine.

An assay for the characterization and quantitative determination of activated cyclophosphamide has been described. The method is based on high reactivity of the kryptaldehyde group in 4-hydroxycyclophosphamide with mercapto compounds to yield 4-(S-R)mercaptocyclophosphamide derivatives. The activated cyclophosphamide can be converted quantitatively to 4-(S-benzyl)mercaptocyclophosphamide with benzyl mercaptan, and the mercapto derivative can be separated by thin-layer chromatography on silica gel with ethyl acetate:methyl ethyl ketone as solvent. Using this assay, significant levels of activated cyclophosphamide in the blood of mice and rats, as well as of humans, were found to be present after cyclophosphamide application. The characterization of 4-(S-benzyl)mercaptocyclophosphamide formed was confirmed by comparing the thin-layer chromatographic and mass spectrometric data on this derivative obtained from an authentic sample of 4-hydroxycyclophosphamide.

Animals↗

PubMedDate not supplied

Pulse cyclophosphamide in the treatment of neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: The effect of pulse cyclophosphamide treatment was retrospectively assessed in 25 systemic lupus erythematosus (SLE) patients with central nervous system involvement. All patients who tested positive for anti-phospholipid antibodies and/or lupus anticoagulant were excluded. RESULTS: Low-dose intravenous cyclophosphamide pulses (500 mg) were administered weekly in all patients. Twenty-four out of 25 patients attained a good response (after a mean of 11 days). Cyclophosphamide was well tolerated in all patients with only minor side effects. None of the patients experienced ovarian failure, cystitis or herpes zoster. CONCLUSIONS: Weekly low-dose cyclophosphamide pulses appear to be safe and effective for the management of neuropsychiatric manifestations in SLE patients without antiphospholipid antibodies.

Adolescent↗

PubMed1996

Prolonged survival of hamster-to-rat pulmonary xenografts by tacrolimus (FK506) and cyclophosphamide.

BACKGROUND: Severe shortage of donor organs in clinical lung transplantation prompted us to investigate the potential use of pulmonary xenografts. The purpose of this study was to determine whether an immunosuppressive regimen of tacrolimus (FK506) and cyclophosphamide would prolong the survival of hamster-to-rat pulmonary xenografts. METHOD: Left lung transplantation was done with male Golden Syrian hamsters used as donors and inbred male Lewis rats as recipients. Control animals (n = 10) received no immunosuppressive drugs whereas experimental animals (n = 6) were treated with tacrolimus and cyclophosphamide. Tacrolimus was administered intramuscularly at a dosage of 2 mg/kg per day on postoperative days 0 to 4, followed by 1 mg/kg per day on days 5 to 29 and 0.5 mg/kg per day on days 30 to 99. Cyclophosphamide (8 mg/kg per day) was administered orally from the day before transplantation to day 8. After transplantation the animals were monitored by chest radiography. Recipient animals were killed at timed intervals (days 60 and 100) and when the chest radiograph showed complete opacification of the transplanted lung. At necropsy, pulmonary xenografts were examined histologically for evidence of rejection, which was graded on a scale of 0 (no rejection) to 4 (severe rejection). Antihamster lymphocytotoxic antibody titer was also measured in recipient animals after transplantation. RESULTS: Pulmonary xenografts in the control animals had a median [correction of medium] survival time of 3 days, whereas the median survival in treated animals was more than 74 days. All pulmonary xenografts in control animals had severe rejection on day 3 after transplantation, whereas those in the treated animals had no rejection on days 60 and 100. The lymphocytotoxic antibody titers in control animals increased from 1:16 before operation to 1:4096 on day 3 (p < 0.01). In the treated animals, the lymphocytotoxic antibody titer on day 21 was 1: 8, which was not different from the preoperative value (1:16). CONCLUSION: These results indicate that a combination of tacrolimus and a short course of cyclophosphamide prolongs the survival of pulmonary xenografts in a hamster-to-rat model.

Animals↗

PubMed1996

Phase I-II study of high-dose busulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation for hematological malignancies: toxicities and hematopoietic recovery.

In a phase I-II study, we evaluated toxicities, tolerability, pace of engraftment, and tumor responses to high-dose bulsulfan and cyclophosphamide followed by autologous peripheral blood stem cell transplantation in patients with hematological malignancies. We treated 51 patients with various hematological malignancies involving the bone marrow with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of autologous peripheral blood stem cells. Stem cells were previously collected during hematopoietic recovery after cyclophosphamide (100 mg/kg) and etoposide (600 mg/m2) followed by G-CSF (5 micrograms/kg/day). Neutrophil recovery (>0.5 x 10(9)/I) was rapid in the majority of patients (median 10 days after transplant, range 7-91 days), resulting in a low number of days with severe neutropenia (median 7 days, range 5-85 days) and with fever (median 5 days, range 1-13 days). Platelet recovery, however, was delayed in 60% of patients. There was one acute transplant-related death (2%). Four patients died of late, presumed infections, pulmonary complications (interstitial pneumonia). Tumor responses were documented in a significant proportion of these patients with high-risk hematological malignancies. We conclude that peripheral blood stem cell transplantation results in rapid recovery of neutrophils but variable recovery of platelets after high-dose busulfan and cyclophosphamide, when stem cells are harvested following priming with cyclophosphamide/etoposide and G-CSF. The regimen is well-tolerated with limited non-hematological toxicities and transplant-related mortality. While significant tumor responses were documented in this trial, the ultimate efficacy of the regimen needs to be further defined.

Adult↗

PubMedDate not supplied

Intravenous cyclophosphamide combined with methylprednisolone in the treatment of severe refractory rheumatoid arthritis: the effect on lymphocytes.

The mode of action of methylprednisolone and cyclophosphamide in the treatment of rheumatoid arthritis still remains unclear. We sought to determine whether methylprednisolone and/or cyclophosphamide affect surface antigens on peripheral blood lymphocytes. Twenty-eight patients with severe refractory rheumatoid arthritis were observed for 12 months. Thirteen patients were treated with an intravenous pulse of methylprednisolone, and fifteen with methylprednisolone combined with cyclophosphamide. The surface antigens of lymphocytes and natural killer (NK) cells isolated from peripheral blood were determined using flow cytometry. The clinical improvement was observed in 16 (57%) patients (8 treated with methylprednisolone and 8 with methylprednisolone/cyclophosphamide). However, after cessation of the treatment in 9 patients, a flare up of the disease was observed. A striking decrease in total lymphocyte count was observed. The percentage of CD3+ and CD3+CD4+ cells remained unchanged. We observed a decrease in the percentage of CD3+CD8+ in patients treated with methylprednisolone/cyclophosphamide. Moreover, the percentage of activated T cells (CD25+ cells and HLA-DR+ cells) was reduced. The depletion of CD8+CD25+ cells was observed after combined treatment. The percentage of CD19+CD5+ was reduced due to the treatment. We also observed a decrease in CD16+CD56+ NK cells. Amelioration of the course of the refractory rheumatoid arthritis was observed in patients treated with both methylprednisolone and methylprednisolone/cyclophosphamide. A stronger effect on lymphocyte phenotype was observed in those given methylprednisolone/cyclophosphamide, but it was not followed by further benefit. On the other hand, the clinical improvement was more stable in methylprednisolone/cyclophosphamide-treated patients. The use of cyclophosphamide should be reserved for patients with rapidly progressing rheumatoid arthritis or life-threatening complications.

Adult↗

PubMed1979

Effect of cyclophosphamide on suppressor cell activity in mice unresponsive to EAE.

Protection against experimental allergic encephalomyelitis (EAE) was induced in susceptible mice of (SJL/J X BALB/c)F1 hybrid, by injection of either mouse spinal cord homogenate, the small mouse basic protein, or Cop 1 in incomplete Freund's adjuvant, before EAE induction. It was demonstrated that the unresponsiveness induced by the three antigens is mediated by suppressor T cells residing in the spleen cell population and can be adoptively transferred to normal syngeneic recipients. Low dose of cyclophosphamide (20 mg/kg) administered 2 days before the encephalitogenic challenge abrogated the unresponsiveness to EAE and reverted the protected mice sensitive to disease induction. Cyclophosphamide was also active on adoptively transferred unresponsiveness, thus donors that had been treated with cyclophosphamide were unable to further transfer unresponsiveness to EAE. These results indicate the elimination by cyclophosphamide of suppressor cells that interfere with the effector mechanisms leading to EAE.

Animals↗