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PubMed2000

Carboplatin and cyclophosphamide in the treatment of metastatic seminoma.

Cisplatin-based chemotherapy is highly effective in advanced seminoma, but at the cost of a considerable toxicity. The response rate of carboplatin is comparable with cisplatin combinations but the relapse rate is higher. Our study assesses the efficacy and the toxicity of the combination of carboplatin and cyclophosphamide in patients with advanced seminoma. Nineteen consecutive patients received 6 cycles of intravenous cyclophosphamide 750 mg/m2 and carboplatin 350 mg/m2, repeated every 21 days. The overall objective response rate was 100%, 11 patients (58%) achieved a complete response and 8 patients (42%) showed a partial response. At median follow up of 4.2 years 3 patients (15%) relapsed. The 2-year disease-free survival and the overall survival are 72 and 94%, respectively. This outpatient treatment was well tolerated and the toxicity was mild. One patient had granulocytopenic fever and one patient had grade 3 cystitis. The combination therapy with carboplatin and cyclophosphamide is an effective and tolerable regimen in advanced seminoma.

Adolescent↗
PubMed1975

A controlled trial of cyclophosphamide in the treatment of proliferative glomerulonephritis.

Cyclophosphamide was administered orally, in a dose just sufficient to depress the white-cell count to 3000-4000 per mm3 (mean 1.5 mg/kg/day), to 27 patients with proliferative glomerulonephritis for 12 months; 26 patients acted as controls. Cyclophosphamide conferred no benefit as judged by mortality, morbidity, renal function (serum creatinine and creatinine clearance) or proteinuria. The side effects of cyclophosphamide included permanent amenorrhoea in five of seven menstruating women. Since no controlled trial has yet shown that any immuno-suppressive drug benefits proliferative glomerulonephritis we question whether such drugs should be administered in this disease except in the course of planned prospective trials.

Amenorrhea↗
PubMed2000

[Assessment of cardiotoxicity of high dose cyclophosphamide with electrocardiographic, echocardiographic, and troponin I monitoring in patients with breast tumors].

BACKGROUND: High-dose cyclophosphamide is the nucleus for virtually all high-dose chemotherapy protocols. Non-hematologic dose-limiting toxicity is represented by acute cardiomyopathy, even fatal in a minority of patients. The pathophysiology of such a cardiotoxicity is still poorly understood. Postmortem studies revealed hemorrhagic myocardial cell death, endothelial damage, and interstitial edema. Recently troponins, in particular troponin I, have been found to represent uniquely sensitive and specific markers of myocyte membrane integrity, thus to increase in response to myocardial cell damage in different clinical settings. METHODS: We performed a multiparametric monitoring in 16 consecutive breast cancer patients undergoing cyclophosphamide, by means of serial ECGs, cardiac enzymes determinations (creatine phosphokinase, MB mass and troponin I) through 0 to 72 hours, and echocardiography at baseline and after 48 hours. RESULTS: Neither overt cardiac failure nor enzyme elevation were recorded. Serial ECGs revealed a reduction in QRS voltage and/or ST segment abnormalities in 6 cases. Echocardiography showed an increase in left ventricular diastolic and/or systolic diameters and volumes in 4 cases but without any decrease in fractional shortening and ejection fraction under normal values: in 2 of them abnormalities of diastolic function (E/A mitral Doppler ratio, isovolumic relaxation time and deceleration time) were also recorded. CONCLUSIONS: Our protocol of cyclophosphamide administration did not cause cardiac toxicity by myocardial cell damage, as analyzed by troponin I levels, thus suggesting that myocyte membrane injury is not the first mechanism of it. ECG (i.e. QRS voltages) and echo-Doppler (i.e. E/A ratio) monitoring lead to hypothesize that endothelial injury and interstitial edema with subsequent reduction in left ventricular diastolic compliance may be the first signs of cardiac dysfunction in this clinical setting.

Adult↗
PubMed2001

Erythropoietin restores the anemia-induced reduction in cyclophosphamide cytotoxicity in rat tumors.

The aim of this study was to examine the impact of anemia prevention by recombinant human erythropoietin (rHuEPO) treatment on the cytotoxicity of cyclophosphamide in solid experimental tumors. Anemia was induced using a single dose of carboplatin (50 mg/kg i.v.) resulting in a long-lasting reduction (30%) of the hemoglobin concentration. In a second group, the development of anemia was prevented by rHuEPO (1000 IU/kg) administered s.c. three times/week starting 7 days before carboplatin application. Four days after carboplatin treatment, tumors (DS-sarcoma of the rat) were implanted s.c. onto the hind food dorsum. Neither carboplatin nor rHuEPO treatment influenced tumor growth rate per se. When tumors were treated with a single dose of cyclophosphamide (60 mg/kg i.p.) 5 days after implantation, a growth delay with a subsequent regrowth of the tumors was observed. In the anemia group, the growth delay was significantly shorter compared with nonanemic controls (13.3 days versus 8.6 days). In the group where anemia was prevented by rHuEPO treatment, growth delay was comparable with that of nonanemic controls (13.3 days). These results suggest that chemotherapy-induced anemia reduces cytotoxicity of cyclophosphamide in tumors, whereas correction of anemia by rHuEPO treatment (epoetin alpha) increases the sensitivity, probably as a result of an improved oxygen supply to tumor tissue.

Anemia↗
PubMedDate not supplied

Mannan mucin-1 peptide immunization: influence of cyclophosphamide and the route of injection.

The mucin MUC1 is greatly increased in breast cancer and is a potential target for immunotherapy. In mice, MUCI conjugated to oxidized mannan (MUC1-mannan fusion protein [M-FP]) targets the mannose receptor and induces a high frequency of cytotoxic T lymphocytes and anti-tumor responses. On this basis, three phase I trials were performed in patients with adenocarcinoma to evaluate the toxicity and the immunologic responses to mannan MUCI. Forty-one patients with metastatic or locally advanced carcinoma of the breast (trial 1), colon (trial 2), and various adenocarcinomas (trial 3) received increasing doses of M-FP (1 to 300 microg). The immunizations were given at weekly intervals (weeks 1 to 3) and repeated in weeks 7 to 9. Cyclophosphamide (to increase cellular immunity) was given on weeks 1 and 4. M-FP was given intramuscularly in trial 1 and intraperitoneally in trial 2. No toxic effects occurred, and delayed-type hypersensitivity responses were present only as a microscopic lymphocytic infiltration. Overall, approximately 60% of the patients had high-titer MUC1 immunoglobulin G1 antibody responses, with the intraperitoneal route yielding approximately 10-fold higher responses. Cellular responses (proliferation, cytotoxic T cells, or CD8 T cells secreting tumor necrosis factor-alpha alphand interferon-gamma in response to MUC1 stimulation in vitro) were found in 28% of the patients, which was similar to that seen without cyclophosphamide. In most patients, disease progressed, but in five it remained stable. In addition, there were no objective responses. M-FP is not toxic and induces immune responses that were amplified by the intraperitoneal route of immunization. Cyclophosphamide was of no benefit.

Adenocarcinoma↗
PubMed2000

Influence of Ukrain and cyclophosphamide administration on HA-1 murine hepatoma and LS lymphoma on aspartic proteinase cathepsin D.

Cathepsin D, the major lysosomal aspartyl proteinase and a mediator of interferon-gamma and tumor necrosis factor-alpha-induced apoptosis, was studied in murine models of LS lymphosarcoma treated by cyclophosphamide (possible apoptosis induction), and HA-1 hepatoma treated by Ukrain (positive antitumor effect). It was found that cyclophosphamide, as well as cyclophosphamide plus Ukrain, increased cathepsin D specific activity in mice with LS lymphosarcoma. Ukrain alone had no effect on cathepsin D activity in LS lymphosarcoma. In HA-1 hepatoma cells cathepsin D activity was not changed compared with intact normal murine liver (day 10) and activity decreased during tumor development (on day 12). Ukrain significantly increased cathepsin D activity in ascitic fluid (day 10) and had a tendency to increase cathepsin D activity in ascitic cells but not to the normal value.

Alkaloids↗
PubMed2000

Clinico-laboratory study of methylprednisolone and cyclophosphamide treatment in patients with multiple sclerosis relapse.

INTRODUCTION: The effect of combined treatment (methylprednisolone and cyclophosphamide) of multiple sclerosis relapse within one year was investigated in an open clinical trial study of 70 patients. The sample comprised subjects shown to have clinically proven multiple sclerosis according to the criteria of C Poser and degree of neurological deficit according to EDSS rating from 2.5 to 6.0 points. MATERIAL AND METHODS: Methylprednisolone (200 mg, i.v., every other day, 10 doses, total course dose 2 g) was administered to 35 patients (mean age 31.34 +/- 1.53 years). Methylprednisolone using the same schedule and cyclophosphamide (200 mg, i.v.) given in the methylprednisolone-free day, 10 doses plus 200 mg i.v. once a month in the first three consecutive months (total course dose 2.6 g) were applied in another 35 patients (mean age 33.22 +/- 1.32 years). RESULTS AND DISCUSSION: The changes of EDSS ratings at the end of months 1 and 12, of the CD+ T-lymphocytes subpopulations and B-lymphocytes from peripheral blood--prior to treatment and between the 5th and 9th week of treatment were compared. The neurological deficit degree according to EDSS dropped significantly (P < 0.01; P < 0.001) after one month of treatment in both groups. At the end of month 12 this indicator reached its baseline value in the group treated only with methylprednisolone while remaining significantly lower in the combined therapy group (P < 0.01). After methylprednisolone and cyclophosphamide application the suppressor/inducer CD8+ T-cells increased significantly in percentage (P < 0.05), while the values of B-lymphocytes decrease significantly (P < 0.05), in contrast to the results from the methylprednisolone-only treatment. CONCLUSIONS: The results clearly indicate the greater efficaciousness of treatment by combining two immunosuppressive drugs.

Adolescent↗
PubMedDate not supplied

[Comparative study of the treatment of autoimmune uveitis with prednisone and with cyclophosphamide and azathioprine].

BACKGROUND: Uveitis is considered an autoimmune disease that compromises any internal structure of eye; its main characteristic is the inflammatory process inside eye. OBJECTIVE: To determine which is the most effective therapy for autoimmune uveitis: cyclophosphamide, azathioprine and prednisone. MATERIAL AND METHODS: Patients between 16 and 65 years old, both sexes, with diagnosis of autoimmune uveitis (anterior, intermediate and posterior). Patients were submitted to clinical history, physical exploration and clinical studies. Their written informed consent was requested and patients were divided into three treatment groups: group 1 (azathioprine) 14 (42.4%) patients; group 2 (prednisone) 15 (45.5%) patients, and group 3 (cyclophosphamide) 4 (12.1%) patients. Blind double observations and assessments at day 0 and at week 1, 2, 4 and 6 of treatment were performed. RESULTS: Out of 33 patients studied, 13 (39.4%) were male and 20 (60.6%) female, the most frequent diagnosis was uveitis due to Toxoplasmosis. With azathioprine 100 mg/day it was observed a better and faster control of inflammation after 6.2 weeks at anterior chamber with p < 0.0001, with prednisone, p = .000, and with cyclophosphamide, p = 135. In the posterior chamber there were no significant inflammatory changes for three groups with p = .353. The most frequent adverse effects occurred in the prednisone group with p < 0.05 in 24.2%, characterized by neutropenia and urinary tract infection. CONCLUSIONS: Azathioprine, 100 mg/day oral during six weeks, is considered the most effective drug, since it demonstrated significant diminishment of inflammatory process in less time, with less side effects and with conservation of visual acuity.

Adolescent↗
PubMed2001

Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide.

Endoglin (EDG; CD105) is a proliferation-associated cell membrane antigen of endothelial cells and is strongly expressed on the tumor-associated angiogenic vascular endothelium. Furthermore, EDG is essential for angiogenesis and a component of the transforming growth factor (TGF)-beta receptor complex. The present three anti-EDG monoclonal antibodies (mAbs), SN6f, SN6j, and SN6k, react strongly with proliferating human endothelial cells but cross-react very weakly with murine endothelial cells. Analysis of Scatchard plot of direct binding of these mAbs to proliferating human umbilical vein endothelial cells showed equilibrium constants of 8.3 x 10(9), 3.1 x 10(9), and 1.0 x 10(9) liter/mol, respectively, for SN6f, SN6j, and SN6k. These mAbs did not react with MCF-7 human breast cancer cells. To facilitate antiangiogenic tumor therapy by these mAbs in animal models, we used human skin/severe combined immunodeficiency (SCID) mouse chimeras bearing tumors of MCF-7. Blood vessels in the chimeras were analyzed by immunostaining with species (human or mouse)-specific anti-CD31 and anti-EDG mAbs including an antihuman EDG mAb termed SN6h. Blood vessels in the completely healed grafted human skins consisted of a mixture of human (43.5%) and murine (56.5%) vessels, whereas only murine vessels were detected in the adjacent murine skins and s.c. tissues. Therefore, murine vessels infiltrate into the human skin grafts from the adjacent murine tissues, whereas the growth of human vessels is limited within the boundary of human skins. Growth of human MCF-7 tumors in the human skin grafts increased the ratio of human:murine vessels. Analyses of the grafted skins before and after tumor transplantation showed that SN6h reacted with tumor-induced angiogenic blood vessels but not with nonangiogenic vessels, whereas antihuman CD31 mAb reacted with both angiogenic and nonangiogenic vessels. The results show that SN6h is capable of distinguishing the tumor-induced angiogenic vasculature from the nonangiogenic vasculature in the present model. Antiangiogenic therapy of the chimeras bearing established MCF-7 tumors was carried out by i.v. administration of a mAb(s) via the tail vein of mice. SN6j and SN6k were effective for suppressing the established tumors, whereas tumor suppression was weaker with SN6f. The results indicate an absence of a direct correlation between antigen-binding avidity and in vivo antitumor efficacy of anti-EDG mAbs and suggest the importance of other factors (e.g., epitopes) in antitumor efficacy. No significant toxicity of the mAbs was detected. Combination of SN6f and SN6k that define mutually nonoverlapping epitopes showed an additive antitumor effect. Combination of SN6j and cyclophosphamide using an antiangiogenic schedule of drug dosing showed synergistic antitumor efficacy. The combination therapy induced lasting complete regression of the established tumors in two of the eight treated chimeras. We examined human and murine blood vessels in large human tumors from the chimeras at the end of therapeutic experiment. The test showed that SN6j therapy resulted in complete suppression of human vessels in the tumors but resulted in only weak suppression of murine vessels. Cyclophosphamide was not effective for suppressing human vessels and only weakly suppressive against murine vessels. Combination of SN6j and cyclophosphamide was effective for completely suppressing human vessels and also effective for partial (i.e., 35%) suppression of murine vessels. The results show that systemic administration of naked antihuman EDG mAbs can suppress established tumors, and the efficacy is markedly enhanced by combining a chemotherapeutic drug using an antiangiogenic schedule of drug dosing. These mAbs should show stronger antitumor efficacy in patients whose tumors depend entirely on human blood vessels.

Angiogenesis Inhibitors↗
PubMed1975

[Modification of hematotoxic effects of cyclophosphamide by anabolid steroids].

Human malignant tumors have been shown to be highly resistant to the chemotherapeutic agents so far available. Since these have to be administered in high doses, hematotoxic effects occur frequently during such treatment. Androgens and anabolic steroids being potent stimulators of normal and of some forms of impaired erythropoiesis, studies were initiated in rats to assess the possibility of a protective role of these steroids against the toxicity of cyclophosphamide. The following results were obtained: 1. A single dose of cyclophosphamide (100 mg/kg) significantly lowered the erythrocyte, reticulocyte, hemoglobin, leucocyte and platelet counts. 2. An initial treatment with nandrolone phenylpropionate signifiantly reduced the decrease of both the erythrocyte and the hemoglobin counts. 3. An initial treatment with metenolone enanthate (Primobolan-Depot) completely prevented the reduction of erythrocytes in appropriate experimental conditions and significantly reduced the decrease of hemoglobins. 4. There was no effect of these steroids on the drop of granulocytes, lymphocytes and platelets. These observations suggest that combination of anabolic steroid therapy with cyclophosphamide therapy may be worthy of clinical trial in patients whose tumors are not subject to growth stimulation by androgenic steroids.

Age Factors↗
PubMed1975

The effects of combined administration of cytembena and cyclophosphamide on the blood count and morphology of nucleoli in peripheral-blood lymphocytes in patients with malignant tumors.

In patients with malignant tumors, changes in the blood count and morphological changes in the nucleoli in peripheral-blood lymphocytes were studied during treatment with Cytembena, Cyclophosphamide, or combinations of both drugs. After administration of Cyclophosphamide (400 mg i.v. daily for 10 days, then 100 mg orally daily), the counts of leukocytes, especially of neutrophils, sank (by 40% maximally), and the erythrocyte count and the haemoglobin content in blood sank moderately. In peripheral-blood lymphocytes, the proportion of ring-shaped nucleoli (stimulable to synthesis of RNA) reversibly sank, and the proportion of micronucleoli (nonstimulable) rose. After administration of Cytembena (400 mg i.v. daily for 10 days, then 200 mg i.m. at intervals of 2--4 days), neither the leukocyte counts nor the relative percentages of lymphocytic nucleoli signigicantly changed; the mean corpuscular haemoglobin content (MCH) transitorily increased (by 10 percent max.). In the group receiving combined cytostatics (Cytembena 400 mg i.v. daily for 10 days, then 200 mg i.m. at intervals of 2--4 days plus Cyclophosphamide 50 mg orally daily), the erythrocyte count and the haemoglobin content in blood sank moderately. In the population of peripheral-blood lymphocytes in this group, there sank the absolute counts of lymphocytes with ring-shaped nucleoli (by 44% max.) and those with micronucleoli (by 33% max.).

Acrylates↗
PubMed2002

[Treatment of progressive multiple sclerosis with cyclophosphamide].

Intravenous (IV) cyclophosphamide is currently used in secondary progressive (SP) and Primary progressive (PP) Multiple Sclerosis (MS) but its efficacy remains uncertain. Furthermore, it is necessary to determine which MS should be successfully treated with IV cyclophosphamide. We retrospectively investigated 111 consecutive patients with progressive MS (21 PPMS and 90 SPMS) treated in an open label fashion with IV cyclophosphamide. We analysed clinical data (gender, age, duration of progression, primary versus secondary MS). The treatment response was assessed by EDSS change after 6 months and 1 year of treatment. The annual relapse average decreased from 1.92 before treatment to 0.39 during the treatment. Age and gender did not influence response to therapy. We did not find any difference of response between PPMS and SPMS. Duration of the progressive phase in SPMS was not a predictive factor of efficacy. A better response was noted in SPMS patients with surimposed relapses than in patients without relapses during the year before treatment (p<0.05). Furthermore, the better response in SPMS patients with relapses before treatment suggests that it is necessary to treat when MS is still in an inflammatory stage.

Adult↗
PubMed2002

Ocular involvement in Takayasu's arteritis: response to cyclophosphamide therapy.

PURPOSE: To report a Takayasu's arteritis (TA) case with an intense ocular involvement and the response to monthly bolus of Cyclophosphamide. METHODS: Case report and literature review. RESULTS: Cyclophosphamide was useful to improve the TA symptoms without any additional treatment and any secondary effects. When this therapy was discontinued the ocular symptoms progressed. CONCLUSION: Although no definitive therapy has been established, Cyclophosphamide intravenous bolus may be useful to improve ocular symptoms of Takayasu's Arteritis, specially in early stages. There are not adequate descriptions in the literature concerning the effect of this treatment on the ocular manifestations of TA.

Adult↗
PubMed2002

HER-2 amplification and topoisomerase IIalpha gene aberrations as predictive markers in node-positive breast cancer patients randomly treated either with an anthracycline-based therapy or with cyclophosphamide, methotrexate, and 5-fluorouracil.

PURPOSE: The purpose of this study is to evaluate HER-2 and topoisomerase IIalpha (topo IIalpha) as candidates for predicting the activity of anthracyclines in the adjuvant treatment of breast cancer patients. EXPERIMENTAL DESIGN: In this study, we evaluated HER-2 and topo IIalpha gene aberrations by fluorescence in situ hybridization in a series of 430 primary breast cancer samples. Samples came from node-positive breast cancer patients randomly treated either with one of two anthracycline-based regimens [full-dose epirubicin-cyclophosphamide (HEC) and moderate-dose epirubicin-cyclophosphamide (EC)] or with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in the context of a Phase III adjuvant therapy trial. Event-free survival comparisons were performed between the three study arms in the subgroups of HER-2-amplified and nonamplified tumors. An explorative analysis was also performed to evaluate the predictive value of topo IIalpha in the cohort of HER-2-amplified patients. RESULTS: HER-2 amplification was observed in 73 of the 354 evaluable samples (21%), whereas topo IIalpha amplification was found in 23 of the 61 evaluable HER-2-amplified tumors (38%). The three event-free survival comparisons were CMF versus HEC, CMF versus EC, and EC versus HEC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were as follows: (a) CMF versus HEC, HR = 1.42 for HER-2-amplified tumors (95% CI, 0.54-3.76; P = 0.48) and 0.84 for HER-2-nonamplified tumors (95% CI, 0.49-1.44; P = 0.53); (b) CMF versus EC, HR = 1.65 for HER-2-amplified tumors (95% CI, 0.66-4.13; P = 0.29) and 0.66 for HER-2-nonamplified tumors (95% CI, 0.39-1.10; P = 0.11); and (c) EC versus HEC, HR = 0.93 for HER-2-amplified tumors (95% CI, 0.31-2.77, P = 0.90) and 1.33 for HER-2-nonamplified tumors (95% CI, 0.82-2.14; P = 0.25). Observed HRs suggest that the anthracycline-based therapy could be more effective than CMF in the subgroup of HER-2-amplified patients, whereas treatments could be equally active in the HER-2-nonamplified cohort. topo IIalpha evaluation suggests that the superiority of anthracyclines over CMF in HER-2-amplified patients could be confined to the subgroup of topo IIalpha-amplified tumors. CONCLUSIONS: HER-2 could have a predictive value for the activity of anthracycline-based regimens in the adjuvant therapy of breast cancer patients. The predictive value of HER-2 would most likely be related to the concomitant amplification of the topo IIalpha gene.

Aged↗
PubMed1975

Peripheral blood lymphocyte nucleoli of rats with Yoshida ascitic sarcoma and the effect of cyclophosphamide.

Changes in the leucocytes, lymphocytes and peripheral blood lymphocyte nucleoli of Yoshida ascitic sarcoma bearing rats untreated and treated with cyclophosphamide were studied. In the course of the growth of Yoshida ascitic sarcoma lymphocytes with "active" nucleoli (compact nucleoli and nucleoli with nucleolonemas) first increased and then, in the terminal stage of the disease, decreased in number. The number of lymphocytes with ring-shaped nucleoli ("reversibly inactive") and micronucleoli was rising throughout the disease. The increase in numbers of micronucleoli in the lymphocytes produced increased values of nucleolar coefficient. After administration of cyclophosphamide to rats with transplanted tumour the number of lymphocytes with both "active" and "reversibly inactive" nucleoli decreased and the number of lymphocytes with micronucleoli increased. The increase in the proportion of micronucleoli also led to increased values of nucleolar coefficient. After cessation of cyclophosphamide treatment and when the signs of the neoplastic disease had disappeared, the changes observed in the white blood cell picture returned to the values before sarcoma transplantation.

Animals↗
PubMed2002

Transitional cell carcinoma of the renal pelvis in a patient with cyclophosphamide therapy for malignant lymphoma: a case report and literature review.

Cyclophosphamide is considered to be a bladder carcinogen and there are many reports of secondary bladder cancer, while only a few cases of upper urothelial cancer have been described. A 59-year-old man, who had received cyclophosphamide therapy for malignant lymphoma, was suffering from gross hematuria and consulted our institute. Computerized tomography (CT), intravenous pyelography (IVP) and retrograde pyelography (RP) revealed a left renal pelvic tumor. Urinary cytology showed class V and radical left nephroureterectomy was performed. Histopathological diagnosis of the left renal pelvic tumor was transitional cell carcinoma, invading the renal parenchyma. He is free from recurrence eight months after surgery. To our knowledge, this is the third case of cyclophosphamide-induced upper urothelial carcinoma reported in Japan, and the twelfth reported in the English literature.

Antineoplastic Agents, Alkylating↗
PubMed1975

Sclerosing alveolitis induced by cyclophosphamide. Ultrastructural observations on alveolar injury and repair.

Adult rats received, intraperitoneally, 20 mg/100 g body weight of cyclophosphamide and were killed 1, 2, 3, 4, 7, 14, 21, and 28 days thereafter. Lung samples were studied by light and electron microscopy. Light microscopy revealed septal and intraalveolar hemorrhages at 2 days and hyaline membranes at 4 days. At 1 to 2 weeks the alveoli were reepithelialized; beyond these intervals there was septal thickening with increased septal cells and interstitial substance. Electron microscopy showed capillary endothelial blebs, membranous pneumocyte injury and sloughing, and severe septal edema at 1 to 2 days. At 4 days some granular pneumocytes appeared altered. At 1 week the alveoli were reepithelialized by prominent granular pneumocytes. Beyond these intervals there was septal thickening with abundant septal cells, debris, collagen, elastin and microfibrils. Some septal elements showed features consistent with "contractile interstitial cells." There was also alveolar collapse indicated by "trapped" granular pneumocytes surrounded by septal cells and fibers. Occasional granular pneumocytes showed large intracytoplasmic cavities. Cyclophosphamide can induce severe injury involving all alveolar components. The partly denuded alveoli are reepithelialized by proliferating granular pneumocytes, thus confirming their importance in alveolar repair. The subsequent development of sclerosing alveolitis suggests that cyclophosphamide may offer a useful experimental model for the study of alveolar injury and repair. The role of the septal "contractile interstitial cells" in the development of septal fibrosis and the possibility that these lesions are reversible remain to be clarified.

Animals↗
PubMed2002

Protective effect of ascorbic acid on cyclophosphamide- induced testicular gametogenic and androgenic disorders in male rats.

AIM: To study the detrimental effects of cyclophosphamide on the testicular androgenic and gametogenic activities through endocrine inhibition and/or induction of oxidative stress in male albino rats and to evaluate the protective effect of ascorbic acid. METHODS: The testicular D5, 3b-hydroxysteroid dehydrogenase (HSD), 17b-HSD, peroxidase and catalase activities along with the levels of malondialdehyde (MDA) and conjugated dienes in testicular tissue were measured for the evaluation of testicular oxidative stress. The plasma testosterone (T) level was measured by immunoassay. Various germ cells at stage VII of spermatogenic cycle were quantified from testicular stained sections. RESULTS: Cyclophosphamide treatment results in a significant inhibition in the testicular D5, 3b-HSD and 17b-HSD activities, a decrease in plasma T level and a diminution in the counts of various germ cells. Moreover, this treatment was also associated with a significant inhibition of the peroxidase and catalase activities along with high levels of MDA and conjugated dienes in the testis. All these changes were reversed by ascorbic acid co-administration. CONCLUSION: Cyclophosphamide treatment at the dosage used caused testicular gametogenic and androgenic disorders as well as induced testicular oxidative stress that can be reversed by ascorbic acid co-administration.

Animals↗