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PubMed2001

Imaging cyclophosphamide-induced intramedullary apoptosis in rats using 99mTc-radiolabeled annexin V.

UNLABELLED: Intramedullary apoptosis of hematopoietic tissue is believed to play a major role in the pathophysiology of myelodysplastic syndrome. Annexin V, a specific marker of the early to intermediate phases of apoptosis, has been applied to the in vitro study of bone marrow aspirates. A noninvasive measure of intramedullary apoptosis in vivo that could serially monitor the clinical progression of myelodysplastic syndrome may be helpful. METHODS: We used 99mTc-radiolabeled annexin V and radionuclide gamma camera imaging to serially study the sites, extent, and severity of intramedullary apoptosis induced by cyclophosphamide treatment. RESULTS: Intravenously administered radiolabeled annexin V localized preferentially in the femur, pelvis, vertebrae, and spleen; increased uptake in these organs was easily visualized as early as 8 h after injection of 100 mg/kg cyclophosphamide in 8- to 10-wk-old animals. Higher doses of cyclophosphamide (150 mg/kg) in animals of the same age increased annexin V uptake in the bone marrow and splenic tissue and delayed recovery of these organs as seen histologically compared with lower doses. Older animals, 5-6 mo old, showed a slower response to cyclophosphamide treatment and delayed recovery of bone marrow and splenic tissues. CONCLUSION: Radiolabeled annexin V can be used to detect and directly quantify the degree of intramedullary and splenic apoptosis in a noninvasive fashion using current clinical radionuclide imaging equipment. Annexin V imaging may be useful clinically in the diagnosis and management of myelodysplastic syndrome.

Aging↗

PubMed2000

Cystatin C in LS lymphosarcoma and HA-1 hepatoma treated with Ukrain and cyclophosphamide and involvement of apoptosis.

The concentration of cystatin C, a cysteine proteinase inhibitor, was measured during the treatment of murine LS lymphosarcoma with cyclophosphamide and HA-1 murine hepatoma with the antitumor drug Ukrain. It was shown that concentrations of cystatin C were very low in both the tumor tissues studied (HA-1 hepatoma cells and LS lymphosarcoma); increased cystatin C concentrations were found only in Ukrain-treated murine hepatoma, suggesting the mechanism of antitumor effect of this drug. Cyclophosphamide treatment in LS lymphosarcoma did not influence the concentration of cystatin C in tumor cells. At the same time, a marked increase in cathepsin B and cathepsin L activity in LS lymphosarcoma was found, indicating the involvement of apoptosis in the mechanism of antitumor action of cyclophosphamide. While the DNA from untreated LS lymphosarcoma was very homogenous and its molecular weight was high, the DNA from tumors of treated mice broke down, giving rise to the ladder figure characteristically produced by cells dying from apoptosis. Evidence was obtained that cyclophosphamide-induced tumor regression was effected by apoptosis.

Alkaloids↗

PubMed1975

The effect of cyclophosphamide on compensatory hypertrophy and some renal functions in rats.

Administration of 20 mg/kg cyclophosphamide to unilaterally nephrectomized rats for a period of two weeks significantly increased the ratio of kidney weight to total body weight. This rise is, however, accountable more by the decrease of total body weight than by weight increase of the kidney. The RNA-DNA ratio in the hyperttrophic kidney after cyclophosphamide did not differ significantly from that found in the hyperttrophic kidneys of controls. The results obtained show that in our experimental lay-out cyclophosphamide did not inhibit significantly the compensatory renal hypettrophy. After cyclophosphamide, the hypertrophic kidney produced urine with lower concentrations of endogenous creatinine, all osmotically active substances and potassium than found in controls.

Animals↗

PubMed2001

[Refractory idiopathic cold agglutinin disease successfully treated with intermittent high-dose cyclophosphamide].

A 56-year-old woman, who had been suffering from idiopathic cold agglutinin disease and treated unsuccessfully with prednisolone and cyclosporine A for 6 months, was referred to our hospital in November 1998. She was given methylprednisolone pulse therapy followed by low-dose cyclophosphamide, but her anemia did not improve. We then began administration of intermittent high-dose cyclophosphamide (1,200 mg/day, every 4 weeks), and this resulted in a dramatic increase of her hemoglobin level and improvement of her symptoms. She is currently receiving 500 mg of cyclophosphamide every 2 months and showing a good response. Intermittent high-dose cyclophosphamide therapy can be an effective treatment for refractory cold agglutinin disease.

Anemia, Hemolytic, Autoimmune↗

PubMed2002

Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer.

This report investigates relationships between the pharmacokinetics and pharmacodynamics of high-dose alkylators used for the treatment of primary breast cancer. Eighty-five women with primary breast cancer involving >or=10 lymph nodes received four cycles of standard-dose chemotherapy followed by a high-dose regimen consisting of: cyclophosphamide (1875 mg/m(2) once daily x 3), cisplatin (165 mg/m(2) given over 72 h), carmustine (600 mg/m(2)), and stem cell transplantation. Dosages were attenuated in patients whose body weight exceeded their calculated ideal weight by >20%. Pharmacokinetics of the high-dose chemotherapeutic agents were evaluated in each patient by collection and analysis of serial blood samples. Area under the concentration time curve (AUC) for cyclophosphamide and carmustine was highly variable (>10-fold inter-patient range) with coefficients of variation > 50%, in contrast to cisplatin exposures (2-fold range; coefficient of variation 12%). The dosing method for overweight patients resulted in significantly lower systemic exposure to cisplatin (P = 0.035). The parent cyclophosphamide clearance on the 1st day of administration was significantly higher in patients who experienced acute cardiac toxicity (n = 5; P = 0.011), whereas carmustine disposition was not found to be different in those developing pulmonary toxicity (n = 25; P = 0.96). Kaplan-Meier analysis (median follow-up of 5.9 years) demonstrated that patients with lower cyclophosphamide AUC (faster parent drug clearance to potentially cytotoxic compounds) survived longer (P = 0.031). Inter-individual differences in the pharmacokinetic disposition of high-dose chemotherapy may explain variability in both response and toxicity. Prospective strategies, which attempt to individualize AUC, should be evaluated in this setting.

Adult↗

PubMed1976

Permeation of cyclophosphamide (NSC-26271) metabolites into tumor cells.

The permeation kinetics of cyclophosphamide and its metabolites were studied with Ehrlich ascites tumor cells, murine L1210 leukemia cells, and mouse L929 fibroblasts at 1 degrees C. In contrast to carboxyphosphamide and nor-nitrogen mustard, an equipartition of cyclophosphamide and 4-hydroperoxycyclophosphamide was observed in these cells. First experiments have been done to study the efflux of cyclophosphamide and 4-hydroperoxycyclophosphamide after incubation until saturation with Ehrlich ascites tumor cells. Cyclophosphamide could be washed out completely, whereas, 4-hydroperoxyclophosphamide shows an apparent retention in the cell at 37 degrees C.

Animals↗

PubMed2003

[A case of recurrent breast cancer with lung metastasis and overexpression of HER2 that responded to UFT and cyclophosphamide combination therapy after sequential treatments with epirubicin, taxanes, and trastuzumab].

We describe a 57-year-old woman who underwent modified mastectomy for right breast cancer (T2N0M0) with overexpression of HER2, in whom lung metastasis developed 3 years after operation. She received sequential chemotherapy, including epirubicin plus cyclophosphamide, docetaxel, paclitaxel and trastuzumab, but the lung lesion progressed after transiently showing a partial response. Oral treatment with UFT and cyclophosphamide was begun as fifth-line treatment. The lung tumor shrank after 2 months, and a partial response has been maintained during continued treatment with UFT and cyclophosphamide. No adverse effects have occurred. We regard combination therapy with oral UFT and cyclophosphamide to be useful for the management of metastatic breast cancer, even in heavily pretreated cases with overexpression of HER2.

Antibodies, Monoclonal↗

PubMed2001

[Weekly cyclophosphamide pulse therapy combined with corticosteroids in the treatment of pemphigus].

OBJECTIVE: To investigate the better regimen of combined cyclophosphamide pulse therapy with corticosteroids in the treatment of Pemphigus. METHODS: Intravenous cyclophosphamide was given weekly in a dosage of 600 mg to those Pemphigus patients whose conditions couldn't be improved by corticosteroids (oral prednisone 1.2-1.5 mg/kg/d) alone. RESULTS: Ten patients with Pemphigus received weekly cyclophosphamide therapy in addition to corticosteroid. Patients conditions improved quickly, without side effects. CONCLUSIONS: Cyclophosphamide weekly pulse therapy combined with corticosteroids is a good regimen in the treatment of Pemphigus.

Adrenal Cortex Hormones↗

PubMed2003

Effect of corticosteroid and cyclophosphamide in IgA nephropathy patients with heavy proteinuria and/or moderate-severe pathological changes.

BACKGROUND: The treatment of immunoglobulin (Ig) A nephropathy remains a subject of controversy. To clarify if it is justified to use corticosteroid and cyclophosphamide in the treatment of IgA nephropathy patients with heavy proteinuria and/or a moderate-severe pathological grading of at least grade II, we retrospectively analyzed the medical data of IgA nephropathy patients in our hospital. METHODS: Totally 60 patients from 370 cases of biopsy-proved IgA nephropathy in our hospital between 1983 and 1999 met the selection criteria and were enrolled into this analysis. These patients received either corticosteroid alone or in combination with cyclophosphamide. The analysis of the progression of renal disease by serum creatinine and changes in the level of proteinuria were based on an on-treatment approach. Kidney survival curve was by Kaplan-Meier analysis and compared among different subgroups. RESULTS: Of the 60 patients, 20 cases (33.3%) (Group 1) reached a complete remission of proteinuria by prednisolone alone. The other cases received a combination therapy with corticosteroid and cyclophosphamide, which resulted in complete remission in 17 cases (28.3%) (Group 2), partial remission in 9 cases (15.0%) (Group 3) and complete resistance in 14 patients (23.3%) (Group 4). The renal survival rate was significantly worse in Group 4 (p < 0.05) as compared with other groups. CONCLUSIONS: We conclude that corticosteroid and combination therapy with corticosteroid and cyclophosphamide was effective treatment in 61.6% (Groups 1 and 2) of IgA nephropathy patients with heavy proteinuria and/or moderate-severe pathological lesions provided their initial serum creatinine level was < or = 3 mg/dl.

Adult↗

PubMedDate not supplied

Cyclophosphamide effect on ultrastructural myocardial changes in rats on low-magnesium diet.

Intraperitoneal cyclophosphamide administration to a total dose of 225 mg/kg body weight during six weeks produced in rat myocardial fibres evident focal degenerative changes in all organelles, and, fairly frequently, significant damage even up to necrosis. The experiment showed that in rats on low-magnesium diet cyclophosphamide produced more intense and more extensive changes than in rats receiving only cyclophosphamide. The extent of the lesions produced with low and high doses of cyclophosphamide was compared and it was observed that the lesions increased with an enlargement of doses of the drug.

Animals↗

PubMed1977

The effect of cyclophosphamide and other drugs on the incidence of pulmonary metastases in mice.

A study was made of the effect of various cytotoxic drugs on the ability of i.v.-injected KHT sarcoma cells to form lung colonies in syngeneic C3H mice. Some enhancement of the number of lung colonies following an i.v. injection was seen following pretreatment of the mice with actinomycin D and mithramycin, while pretreatment with vinblastine, bleomycin, methotrexate, cytosine arabinoside, or 5-fluorouracil had little or no effect on lung colony formation. Pretreatment of the mice with cyclophosphamide, however, greatly increased lung colony formation (by a factor of approximately 100). This enhancement in lung colony formation was maximal when the drug was given 24 hr prio to the injection of tumor cells, but was seen as early as 2 hr and persisted as long as 8 weeks prior to the tumor cell injection. The degree of enhancement of lung colony formation was related to the dose of cyclophosphamide and was present in weaning as well as adult mice. This enhancement was not significantly reversed by anticoagulation with either aspirin or warfarin. Immunosuppression by whole-body irradiation did not affect the number of lung colonies seen in cyclophosphamide-treated mice. The mechanism by which cyclophosphamide enhances metastatic tumor growth within the lung is not known. The major effect, however, does not appear to be mediated either by specific immunological or clotting factors.

Age Factors↗

PubMed2003

[Effect of cyclophosphamide on bone remodeling in rats].

Neoplasms, with or without metastases in bones, can induce pathological bone remodeling, leading to systemic bone resorption and hypercalcemia or osteomalacia and normocalcemia. The aim of the present study was to investigate the effect of a cytostatic--cyclophosphamide on the skeletal system in rats. The experiments were carried out in male Wistar rats with initial body weight of 212-229 g, divided into 3 groups (n = 6): I--Control, II--Cyclophosphamide (10 mg/kg m.c. i.m. daily for 14 days, and after a 7-day break, for 7 days), III--Cyclophosphamide (20 mg/kg m.c.p.o. daily for the initial 14 days). After 30 days of the experiment, the animals were killed and bone mass, length and diameter of long bones, mineral content in bones, transverse cross-section surfaces of the cortical diaphysis and of the marrow cavity, transverse growth, width of endosteal and periosteal osteoid in the tibia, width of trabeculae, width of epiphyseal cartilage and mechanical features of the femur were examined. Cyclophosphamide caused disorders of bone tissue remodeling. Decreases in bone mass, length, diameter, mineral content in bones, width of trabeculae in the femur, transverse growth, width of osteoid, transverse cross-section surface of the cortical diaphysis, and worsening of mechanical properties of the femur were observed.

Animals↗

PubMed2003

[Cyclophosphamide pulse therapy for pediatric systemic sclerosis].

We encountered three patients with pediatric systemic sclerosis. Patient 1 had systemic scleroderma, pigmentation and interstitial pneumonia at the age of 10 years. Nine months after disease onset, she was treated with intravenous cyclophosphamide pulse therapy as induction therapy. After the initial treatment, the following clinical manifestations were dramatically improved: interstitial pneumonia, scleroderma and total skin score. Patient 2 was a 7-year-old girl, who complained of systemic scleroderma and pigmentation, and was found to have pulmonary hypertension. Six months after disease onset, she was administrated intravenous cyclophosphamide pulse therapy. Her scleroderma and total skin score were improved and the pulmonary hypertension did not deteriorate. Patient 3 was a 15-year-old girl. Her initial treatment was vitamin E alone. She was admitted to our hospital two and half years after disease onset. Although she was given immunosuppressive therapy including cyclophosphamide, the severe condition of persisted, and she died after five months. It became possible for patient 1 and 2 to achieve and maintain a marked improvement of the clinical manifestations as a result of cyclophosphamide pulse therapy early in the course of the disease. We further observed that their total skin score was decreasing while the clinical manifestations improved.

Adolescent↗

PubMed1992

Pathogenesis of wasting disease after cyclophosphamide treatment of neonatal mice.

Cyclophosphamide is a potent immunosuppressive agent and is being widely used in organ transplantation. The effects of this anti-rejection drug on lymphoid organs are poorly understood. Newborn Swiss mice injected with various doses of cyclophosphamide suffered from wasting disease at 4 weeks post treatment. The incidence of wasting disease was dose dependent. Haematological picture of the wasting animals revealed leukocytosis of variable degree. Lymphocyte/granulocyte ratio was not inhibited. The cyclophosphamide treatment caused shrinkage of lymphoid organs. Bone marrow showed degeneration of haematopoietic cells. The failure to sustain lymphopoiesis by the potential lymphoid sites following cyclophosphamide treatment and the associated immunological insufficiency resulted in the fatal wasting disease.

Animals↗

PubMed1992

[Good results of cyclophosphamide in steroid toxicity in the treatment of nephrotic syndrome caused by minimal-lesion glomerulopathy in childhood].

The effect of cyclophosphamide therapy was evaluated in the treatment of children with nephrotic syndrome due to minimal lesions. Most of the children, 37 out of 43, presented with frequent relapsing nephrotic syndrome. Cyclophosphamide was given in a dose of 3 mg/kg body weight/day for a period of 8 weeks. Two patients received two courses, one patient received three courses. Only one patient, who was steroid-resistant, did not respond to cyclophosphamide therapy (therapy was, however, stopped after 3 weeks because of haemorrhagic cystitis). 57% of the patients were still in remission after 18 months (n = 37) and 50% after 30 months (n = 34). A haemorrhagic cystitis developed in 3 patients and leucopenia in 2 patients. From this study, which confirms data reported in literature, it can be concluded that cyclophosphamide has a beneficial effect in children with minimal lesion nephrotic syndrome and steroid toxicity.

Adolescent↗

PubMed2005

Cyclophosphamide therapy for MS.

Cyclophosphamide has been widely studied for the treatment of MS and the effective stabilization of selected patients on therapy has been suggested in several studies. This drug has selective effects on the immune response, such as suppression of helper Th1 activity and enhancement of helper Th2 responses; both of these processes are thought to be involved in the beneficial effect of cyclophosphamide in MS. Over the years, especially with the advent of magnetic resonance imaging (MRI), there has been an improved understanding of the profound anti-inflammatory effect of cyclophosphamide, evidenced by its effect on clinical relapses and contrast-enhancing lesions on MRI. Toxic effects on the bladder and the risk of malignancy prevent the widespread use of cyclophosphamide in early MS; however, it can be dosed safely and is usually well tolerated in actively progressing relapsing-remitting or early secondary progressive MS cases that are unresponsive to beta interferon and glatiramer acetate.

Adolescent↗

PubMed1991

The Canadian cooperative trial of cyclophosphamide and plasma exchange in progressive multiple sclerosis. The Canadian Cooperative Multiple Sclerosis Study Group.

To find out whether non-specific immunosuppression is beneficial in multiple sclerosis (MS) a randomised, placebo-controlled, single-masked trial was carried out in nine university centres. 168 patients with clinically or laboratory-supported definite MS in progressive phase (deterioration by at least 1.0 on the expanded disability status scale [EDSS] in the previous year) were randomised to receive intravenous cyclophosphamide and oral prednisone (n = 55); daily oral cyclophosphamide, alternate day prednisone (22 weeks), and weekly plasma exchange (20 weeks) (n = 57); or placebo medications and sham plasma exchange (n = 56). All patients were followed for at least 12 months (mean 30.4 months) by a monitoring neurologist, who was aware of treatment allocation, and an evaluating neurologist, who was not. The primary analysis was a comparison of rates of treatment failure (worsening of evaluating neurologist's assessment of EDSS by 1.0 or more on two consecutive 6-monthly assessments). There were no significant differences among the groups in this primary analysis (19 [35%] treatment failures with cyclophosphamide; 18 [32%] with plasma exchange; 16 [29%] with placebo). Nor were there any differences in the proportions improved, stabilised, or worsened at each 6 month assessment or in the mean change in the EDSS at the final assessment (0.81 cyclophosphamide; 0.69 plasma exchange; 0.69 placebo). A slight trend favouring the plasma exchange group at 12-24 months of follow-up was not sustained at the final assessment. This study fails to confirm previous reports that immunosuppressive treatments result in stabilisation or improvement in progressive MS.

Adult↗

PubMed1991

Longterm followup after treatment of polyarteritis nodosa and Churg-Strauss angiitis with comparison of steroids, plasma exchange and cyclophosphamide to steroids and plasma exchange. A prospective randomized trial of 71 patients. The Cooperative Study Group for Polyarteritis Nodosa.

We attempted to define the most effective treatment for polyarteritis nodosa and Churg-Strauss angiitis, with a prospective, randomized, multicenter trial of cyclophosphamide in conjunction with corticosteroids and plasma exchanges, compared to corticosteroids and plasma exchanges. A total of 71 patients who fulfilled clinical, histological and/or arteriographic diagnostic criteria were randomly designated to receive either prednisone and plasma exchanges (group A, n = 39) or cyclophosphamide, prednisone and plasma exchanges (group B, n = 32). The end points of the study were control of the disease (recovery and remission) and death. Upon study entry clinical and laboratory features did not differ in the 2 groups. Treatment was stopped in 19 patients because of ineffectiveness in 10 (9 in Group A) and side effects in 9 (8 in Group B). Initial control of the disease was similar in both groups. At 5 years, 27 patients had completely recovered and 14 patients were in clinical remission. The cyclophosphamide-prednisone-plasma exchange association was beneficial in preventing relapses during longterm followup. Nineteen deaths were reported during the followup period. There was no difference between the 10 year cumulative survival rates of the 2 groups (respectively, 72 and 75%). Thus, the association of cyclophosphamide with corticosteroids and plasma exchanges reduced the incidence of relapses and improved the quality of the clinical response to therapy.

Adolescent↗