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At least 1,243 records · Page 69Linked to original sources
PubMed1994

The cardioprotector ADR-529 and high-dose epirubicin given in combination with cyclophosphamide, 5-fluorouracil, and tamoxifen: a phase I study in metastatic breast cancer.

The purpose of this study was to determine the maximal tolerable dose (MTD) of epirubicin and ADR-529 given in combination with cyclophosphamide, 5-fluorouracil, and tamoxifen. A total of 64 breast cancer patients with locally advanced disease or a first metastatic event were included. Using fixed doses of cyclophosphamide, 5-fluorouracil, and tamoxifen, cohorts of ten patients were treated with escalating doses of epirubicin and ADR-529. With the use of protocol criteria specifying evaluation after the first course, the MTD was not reached. Dose reductions carried out due to hematologic toxicity during the first four courses made it impossible to escalate doses of epirubicin beyond 80 mg/m2 given together with ADR-529 600 mg/m2. The vascular toxicity of ADR-529 necessitated central venous access in a number of patients. For phase III evaluation of ADR-529 given together with cyclophosphamide, epirubicin, 5-fluorouracil, and tamoxifen (CEF/TAM) we recommend using epirubicin/ADR-529 at 60/600 mg/m2. Together with evaluation of the cardioprotective properties of ADR-529, we recommend evaluating the impact of ADR-529 on the efficacy of cytotoxic therapy and investigating further the toxicity of ADR-529.

Adult↗
PubMed1992

Pharmacokinetics and metabolism of cyclophosphamide in paediatric patients.

The pharmacokinetics and metabolism of cyclophosphamide were studied in nine paediatric patients. Plasma samples were obtained from eight subjects and urine was collected from six children during a 24-h period after drug administration. Cyclophosphamide and its major metabolites phosphoramide mustard (PM), carboxyphosphamide (CX), dechloroethylcyclophosphamide (DCCP) and 4-ketocyclophosphamide (KETO) were determined in plasma and urine using high-performance thin-layer chromatography-photographic densitometry (HPTLC-PD). Cyclophosphamide (CP) was nearly, if not completely, cleared from plasma by 24 h after its administration. The plasma half-life of CP ranged from 2.15 to 8.15 h; it decreased following higher doses and was shorter than that previously reported for adult patients. Both the apparent volume of distribution (0.49 +/- 1.4 l/kg) and the total body clearance (2.14 +/- 1.4 l m-2 h-1) increased with increasing dose. Renal clearance ranged between 0.12 and 0.58 l/h (mean, 0.43 +/- 0.19 l/h). Between 5.4% and 86.1% of the total delivered dose was recovered as unchanged drug in the urine. The major metabolites identified in plasma and urine were PM and CX. One patient appeared to be deficient in CX formation. This study suggests that there is interpatient variability in the pharmacokinetics and metabolism of CP in paediatric patients. The shorter half-life and higher clearance as compared with adult values indicate faster CP metabolism in children.

Absorptiometry, Photon↗
PubMed1992

Gut protection by cyclophosphamide "priming" in patients receiving high-dose melphalan--effect of drug scheduling.

A "priming" injection of cyclophosphamide (400 mg/m2 given i.v. on day -7) has been shown to reduce intestinal permeability and thus gut toxicity in patients receiving high-dose melphalan. To determine the optimal timing for this injection, patients receiving 200 mg/m2 melphalan with an autologous bone marrow transplant were randomly assigned to receive cyclophosphamide at 5, 7 or 9 days before the melphalan. The median percentage of [51Cr]-ethylenediaminetetraacetic acid excretion was similar (9.1% vs 7.1% vs 7.7%, respectively), with equivalent duration of WHO grade 2-4 mucositis and diarrhoea being recorded for each group. Thus, the timing of the cyclophosphamide prime is not critical, and the priming injection may be given between 5 and 9 days prior to high-dose melphalan.

Bone Marrow Transplantation↗
PubMed1992

Pilot study of escalating doses of carboplatin and cyclophosphamide in patients with advanced cancer.

In all, 18 patients with histologically proven advanced cancer received 400 mg/m2 carboplatin (CBDCA) plus 800 mg/m2 cyclophosphamide (level 1), and 14 others received 550 mg/m2 CBDCA plus 1100 mg/m2 cyclophosphamide (level 2). A maximum of six cycles was given if a response occurred. The dose-limiting toxicity was myelosuppression, with neutropenia being more marked than thrombocytopenia. At level 2, patients experiencing a febrile-neutropenic event showed a mean 24-h urinary creatinine clearance value of 1.1 ml/s (95% confidence limits 0.8-1.4 ml/s), whereas in those who remained afebrile it was 1.7 ml/s (95% confidence limits, 1.3-2.0 ml/s). This difference was significant (P less than 0.01). Other toxicities were only mild. Creatinine clearance is a predictor of febrile episodes after treatment with high doses of CBDCA and cyclophosphamide. We are now conducting a study using human granulocyte colony-stimulating factor to reduce the incidence of neutropenia with escalating doses of these drugs in an attempt to prevent febrile events.

Aged↗
PubMed1994

Variability in the pharmacokinetics of cyclophosphamide, methotrexate and 5-fluorouracil in women receiving adjuvant treatment for breast cancer.

A total of 23 women with stage II breast cancer receiving adjuvant cyclophosphamide, methotrexate and 5-fluorouracil had detailed pharmacokinetic monitoring performed on the first and third courses of therapy. The area under the concentration time curve (AUC) of each of these three drugs varied by a factor of 3-4 among patients. No systematic change in pharmacokinetics between the first and third courses was seen for cyclophosphamide, methotrexate or 5-fluorouracil, and the mean AUC for each of the three drugs did not change. However, significant intrapatient variability in drug pharmacokinetics was observed for all three drugs such that the AUC, clearance and half-life in an individual on the third course could not be reliably predicted from data generated on the first course. On the basis of these results, cyclophosphamide, methotrexate, and 5-fluorouracil pharmacokinetic data from one treatment would not be useful information from which the doses of subsequent courses could be determined.

Adult↗
PubMed1995

Interleukin-2 gene therapy of residual EL-4 leukaemia potentiates the effect of cyclophosphamide pretreatment.

Experiments were designed to investigate a possible therapeutic role of interleukin-2 (IL-2) gene transfer in the model of murine (EL-4) leukaemia pretreated with cyclophosphamide. It has been found that i.p. pretreatment of the leukaemic mice with cyclophosphamide, followed by i.v. administration of irradiated cells, genetically engineered to produce IL-2 and used as a source of the cytokine (IR-IL-2 cells), cured a substantial percentage of the leukaemic mice. Neither treatment with cyclophosphamide nor administration of the IR-IL-2 cells alone had any significant therapeutic effect. Labelling of the EL-4 and IR-IL-2 cells with different fluorescent cell linkers followed by i.v. injection and detection of the labelled cells in cryostat sections of various organs has shown that both cell populations can be detected almost exclusively in the red pulp of the spleen, close to the white pulp nodules, thus providing the possibility of short-range local interactions among the IL-2-producing cells, IL-2-responsive defence effector cells and EL-4 leukaemia targets.

Animals↗
PubMed1997

Complications of cyclophosphamide therapy.

Cyclophosphamide is a powerful immunosuppressive agent that is commonly used clinically to treat neoplastic and inflammatory diseases affecting various sites, including the head and neck. The pharmacology of cyclophosphamide is reviewed with an emphasis on its toxicities and strategies for minimizing therapeutic adverse effects. Principles of therapy are discussed and illustrated by the use of cyclophosphamide in the treatment of Wegener's granulomatosis, a form of systemic vasculitis with prominent head and neck manifestations.

Bone Marrow↗
PubMed1989

Therapeutic efficacy of human recombinant interleukin-2 (TGP-3) alone or in combination with cyclophosphamide and immunocompetent cells in allogeneic, semi-syngeneic, and syngeneic murine tumors.

The potential for a recombinant human interleukin-2 (rIL-2, TGP-3) alone, in combination with cyclophosphamide, and in combination with cyclophosphamide and normal immunocompetent cells to manifest biological activity in vivo was tested using allogeneic, semi-syngeneic, and syngeneic tumor-host systems in mice. The biological activity of rIL-2 was evaluated by the inhibition of the growth of tumors and the inhibition of metastases in short-term assays and, in long-term assays, the prolongation of the survival time of mice bearing subcutaneously (s.c.) or intradermally transplanted tumors. rIL-2 was injected s.c. daily continuously for up to 40 days or intermittently two to four times into mice bearing established tumors. In the short-term assays, the dose and schedule dependence of activity of rIL-2 alone was significantly manifested against sarcoma 180 in ICR mice (allogeneic) by the regression of the tumor, and was confirmed against Meth-A fibrosarcoma in BALB/c mice (syngeneic) by retarding the growth of the tumor. When assessed using these tumor, it was found that the antitumor activity of rIL-2 was schedule-dependent: the growth of tumors was more significantly suppressed when rIL-2 was injected every day for 10 days, starting on the 7th day after tumor transplantation, than when rIL-2 was injected five times every other day or twice every 5th day, even if the total amounts of rIL-2 injected were same. The continuous injection for 10 days was considered to be a standard regimen and the daily effective doses of rIL-2 were 5, 10, and 25 micrograms/mouse. Using the standard regimen and the effective doses, the activity of rIL-2 alone was also observed against two other syngeneic tumors: Colon carcinoma 26 in BALB/c mice, by retarding the growth of the tumor, and Lewis lung carcinoma in C57BL/6 mice by reducing the formation of lung metastases. When assessed using M5076 reticulum cell sarcoma, in a long-term assay, the activity of rIL-2 alone was not manifested in C57BL/6 mice (syngeneic) even when rIL-2 was injected for a long period (20 days) but it was observed in BDF1 (semi-syngeneic) mice. On the other hand, it was found that rIL-2 was effective in combination with cyclophosphamide in prolonging the survival time of C57BL/6 mice bearing the tumor.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

Cyclophosphamide modifies the induction kinetics but not cell types and cytotoxic mechanisms of antitumor cells elicited with OK-432 plus attenuated tumor cells.

The present study was designed to examine whether the antitumor cells induced by treatment with mitomycin-C-treated EL4 cells (EL4MMC) plus OK-432 plus cyclophosphamide differed from those induced by treatment with EL4MMC plus OK-432 in terms of their cell types and antitumor mechanisms. Antitumor activity of peritoneal exudate cells (PEC) from mice receiving either treatment was nonspecific, and inhibition of their target cell growth increased for up to 24 h. Macrophage toxin, silica and trypan blue abrogated the activity in vitro and in vivo, respectively. The activity of the PEC was inhibited with inhibitors of the arachidonic acid cascade, such as dexamethasone, 4-bromophenacyl bromide and nordihydroguaiaretic acid but not esculetin, ibuprofen, indomethacin and BW755C. NG-monomethyl-L-arginine, a specific competitive inhibitor of the L-arginine-dependent nitric oxide synthesis, also inhibited the activity. These results and morphological observations indicated that antitumor cells in the PEC from mice receiving either treatment were macrophages, and that their activity was closely related to the arachidonic acid cascade and to nitric oxide. Antitumor activity of the PEC spontaneously decayed in vitro and this decay was inhibited by the addition of OK-432 or lipopolysaccharide. On the other hand, cyclophosphamide sustained the appearance of antitumor cells in mice treated with EL4MMC plus OK-432. Therefore, cyclophosphamide treatment did not modify cell types and cytotoxic mechanisms of antitumor cells elicited with EL4MMC plus OK-432, but did modify the induction kinetics of such antitumor macrophages.

Animals↗
PubMedDate not supplied

Effects of rotational stress on the effectiveness of cyclophosphamide and razoxane in mice bearing Lewis lung carcinoma.

The effects of conventional vs protected housing, and those caused by the periodic application of a psychological stressor (rotational stress, spatial disorientation) on mice kept in a protected housing, with spontaneous tumor metastasis have been determined in mice implanted with Lewis lung carcinoma as a function of tumor inoculum size and response to treatment with cyclophosphamide and razoxane. With a reduced inoculum size, tumor takes do not occur in mice kept in the protected housing, but do occur with spatial disorientation. With a larger inoculum size, tumor takes occur in all untreated mice, and the weight of spontaneous lung metastasis is significantly increased by spatial disorientation. For mice in protected housing, cyclophosphamide results in the absence of macroscopically detectable tumors in all of the treated mice, whereas the use of spatial disorientation abolishes this therapeutic action. The antimetastatic effects of razoxane are also reduced by rotational stress. These results indicate that housing conditions and a psychological stressor can control tumor takes and metastasis formation. They also indicate that host's antitumor resistance effectors, which are susceptible to neuroendocrine modulation by environmental and psychological stressors, participate to determine the effectiveness of the treatment with a cytotoxic (cyclophosphamide) and antimetastatic (razoxane) antitumor drug.

Animals↗
PubMed1996

Dose-ranging evaluation of the antiemetic efficacy of intravenous dolasetron in patients receiving chemotherapy with doxorubicin or cyclophosphamide.

Selective 5-HT3 antagonists have proven to be safe and effective for the prevention of chemotherapy-induced nausea and vomiting. Dolasetron is a new highly selective addition to this class of antiemetics that has been shown to have significant antiemetic activity in patients receiving cisplatin-containing regimens. This pilot study was designed to evaluate the antiemetic efficacy of dolasetron in cancer patients receiving doxorubicin and/or cyclophosphamide. This study used an open-label, non-randomized design to evaluate the efficacy and safety of intravenous dolasetron in the prevention of emesis in patients receiving doxorubicin (25-75 mg/m2) and/or cyclophosphamide (400-1200 mg/m2). Sixty-nine patients received a single, intravenous dose of dolasetron over 15-20 min beginning 30 min prior to the start of chemotherapy. Dose levels of dolasetron studied were: 0.3, 0.6, 1.2, 1.8 and 2.4 mg/kg. Patients were monitored for emesis, nausea and adverse events for 24h after the start of chemotherapy. Overall, 61% of patients experienced complete control of emesis. No significant trend towards increased antiemetic efficacy (P = 0.076) or nausea control with increasing dolasetron dose was noted, although the power to detect significant differences was limited by the small number of patients on the 0.3-mg/kg and 2.4-mg/kg dose levels. Age, gender, and type of chemotherapy were significant predictors of complete antiemetic control. Adverse events were generally mild and included headache, chills, lightheadedness, fever, diarrhea, dizziness, and asymptomatic prolongation of ECG intervals. Intravenous dolasetron is safe and effective in the prevention of emesis induced by doxorubicin and/or cyclophosphamide.

Adult↗
PubMed1990

Effects of indomethacin, cyclosporin, cyclophosphamide, and placebo on collagen-induced arthritis of mice.

The long term effects of indomethacin, cyclosporin, cyclophosphamide, and placebo on collagen-induced arthritis in mice were tested under two different treatment protocols. A prophylactic experiment examined the effects of the daily drug administration for 180 days beginning one day before the first collagen injection. Under this dosage schedule, cyclophosphamide and cyclosporin decreased the severity of arthritis, while indomethacin did not. A therapeutic protocol examined the effects of these same drugs when daily administration was delayed until the animals had active disease at 78 days after the first collagen injection. Under this protocol, all three drugs reduced the progression of disease. In both protocols, the most significant suppression of arthritis was seen in animals receiving cyclophosphamide which was associated with a decrease in anti-collagen antibody levels. Collagen-induced arthritis in mice should be further investigated as a model to study the long term effects of "slow-acting" anti-rheumatic drugs.

Animals↗
PubMed1993

Effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis in rats.

The prophylactic and therapeutic effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis (CIA) were evaluated in DA rats. Prophylactic treatment with cyclosporin A and cyclophosphamide suppressed the arthritis incidence, clinical inflammation, destructive bone changes, and development of anti-collagen antibody in DA rats subsequently injected with porcine type-II collagen. Therapeutic treatment with cyclosporin A and cyclophosphamide had a definite suppression on established CIA when started 21 days after the initial collagen injection, but the suppression was less marked than that of prophylactic treatment. Gold had no impact on CIA in DA rats when administered either prophylactically or therapeutically.

Animals↗
PubMed1995

Reversible hepatic dysfunction in association with cyclophosphamide therapy.

A 5.5-year-old child with nephrotic syndrome was treated with cyclophosphamide. After 9 weeks of therapy she developed jaundice and abnormal liver function tests. No infective aetiology was found and the abnormal liver function tests resolved within 5 weeks of discontinuing cyclophosphamide. Cyclophosphamide has rarely been reported to cause liver dysfunction, but not in children treated for nephrotic syndrome, and paediatricians should therefore be aware of its potential for inducing reversible hepatic dysfunction.

Child, Preschool↗
PubMed1977

Therapeutic studies with BCG, cyclophosphamide and surgery alone and in combination on the autochthonous mammary carcinoma of the rat.

In a randomized study the effects of BCG, cyclophosphamide and surgery alone and in combination on the mammary carcinoma (induced by 7,12-dimethylbenz(a)anthracene) of the rat were investigated. Surgical excision of the tumours increased the survival time. Cyclophosphamide retarded growth of tumours and delayed the appearance of relapses compared to surgery. A single, intravenous injection of BCG (10(7) viable organisms) showed no statistically significant retardation of tumours. Immunotherapy with BCG could not increase the effectiveness of cyclophosphamide or surgery or their combination.

Animals↗
PubMed1988

Effect of cyclophosphamide on the candidacidal activity of rabbit peritoneal macrophages.

Single and repeated intravenous administration of cyclophosphamide significantly decreased the candidacidal activity of rabbit peritoneal macrophages. Using higher doses of the drug, a more pronounced decrease, persisting up to 10 d, was observed. The phagocytic index has not changed significantly 10 d after cyclophosphamide injection as compared with controls. No changes in the phagocytic activity were recorded. The decreased candidacidal activity may be one of the causes of serious microbial infections in cyclophosphamide-treated patients.

Animals↗
PubMed1998

Apoptosis and beta-cell destruction in pancreatic islets of NOD mice with spontaneous and cyclophosphamide-accelerated diabetes.

Autoimmune-mediated destruction of pancreatic islet beta cells leads to insulin-dependent diabetes in non-obese diabetic (NOD) mice. Although both direct cytotoxic T cell- and indirect cytokine-, nitric oxide- or free radical-mediated mechanisms induce beta-cell apoptosis in vitro, beta-cell death in vivo in spontaneous autoimmune diabetes is not well-characterized. Furthermore, whether beta cells die gradually, or rapidly in the late pre-clinical stage, is a question of current interest. To investigate beta-cell death in vivo, we measured the frequency and intra-islet localisation of apoptosis, defined as DNA strand breaks by the terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) technique, during spontaneous and cyclophosphamide-accelerated diabetes in NOD mice. In spontaneous diabetes, the frequency of apoptosis in islets correlated with the progression of beta-cell destruction with age. Although apoptosis was detected at low frequency within the reduced insulin-positive islet area of pre-diabetic mice at 90 days of age, it was rarely co-localised to beta cells. After acceleration of beta-cell destruction with cyclophosphamide, the frequency of apoptosis reached maximum at 12 days, at which time 3.2 % of apoptotic cells were beta cells. Apoptosis was most frequent in the insulin-negative islet area comprised of mononuclear cell infiltrate and was localized to CD8+ T cells. The rarity of detectable apoptotic beta cells in spontaneous pre-diabetic mice with pronounced insulitis and reduced insulin-positive islet areas most likely reflects the rapid clearance of apoptotic beta cells. Our findings are more consistent with gradual destruction of non-renewable beta-cells in spontaneous diabetes, than with their rapid, accelerated destruction (as after cyclophosphamide) in the late pre-clinical stage.

Aging↗
PubMed1996

Cyclophosphamide-induced apoptosis induces phocomelia in the mouse.

Phocomelia (absence of upper fore and/or hind limbs) was induced in mouse fetuses using cyclophosphamide. On day 11 of gestation, pregnant mice were injected intraperitoneally with 10 ml/kg of saline containing cyclophosphamide (CP) at a dosage of 20 mg/kg body weight. On day 18, the fetuses were removed by Caesarean section from dams given CP on day 11 and were examined for external anomalies. Of 22 fetuses from CP-treated dams, 13 were dead or absorbed, but the surviving 9 fetuses were found to have phocomelia with various other external anomalies. In order to examine the direct cytotoxic effect of CP on fetal limb buds, fetuses were removed at 8, 16, 24, and 48 h after CP administration on day 11, revealing the presence of frequent pyknotic nuclei and apoptotic bodies in hematoxylin and eosin (H & E) preparations. Cell-nuclei and apoptotic bodies were frequently observed by nick end-labeling in limb buds. Transmission electron microscopy demonstrated the typical changes of apoptosis. DNA extracted from the fetal limb buds submitted to CP was analysed by agarose gel electrophoresis, showing the ladder pattern characteristic of internucleosomal cleavage. These findings suggest that cyclophosphamide causes apoptosis in mouse fetal limb buds and that this process induces the external anomalies of phocomelia.

Animals↗