SEARCH · PubMed Health

Results for “CYCLOPHOSPHAMIDE”

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

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

At least 433 records · Page 24Linked to original sources

PubMed1997

Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer.

PURPOSE: A potential application of hematopoietic growth factors is to obtain an increased dose-intensity. This can be achieved by either higher doses of chemotherapy with standard intervals, or by standard doses with shorter intervals. The potential of these approaches has not been investigated systematically. PATIENTS AND METHODS: In a randomized, multicenter study, 49 advanced breast cancer patients were treated with granulocyte colony-stimulating factor (G-CSF) and either increasing doses of epirubicin and cyclophosphamide with fixed intervals (arm one) or progressively shorter intervals with fixed doses of epirubicin and cyclophosphamide (arm two). A cohort of at least six patients was studied at each interval/dose. A more intensified interval/dose was given if less than 50% of patients encountered a dose-intensity limiting criterium (DILC) in the first three courses. RESULTS: In arm one, epirubicin 140 mg/m2 and cyclophosphamide 800 mg/m2 every 21 days was too toxic. Subsequently, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 was tested with two of 10 patients encountering a DILC. All initial DILCs consisted of febrile neutropenia. In arm two, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely with 14- and 12-day intervals. In the 10-day interval, eight of 12 patients completed the first three cycles without a DILC. In the 8-day interval, seven of eight patients encountered a DILC. Incomplete neutrophil recovery, and to a lesser extent stomatitis, were dose-limiting. CONCLUSION: In combination with G-CSF, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 every 21 days was feasible (projected dose-intensity, 40 mg/m2/wk and 233 mg/m2/wk, respectively). Epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely every 10 days, allowing a projected dose-intensity of 52.5 mg/m2/wk and 350 mg/m2/wk, respectively.

Adult↗

PubMed2003

Pentostatin and cyclophosphamide: an effective new regimen in previously treated patients with chronic lymphocytic leukemia.

PURPOSE: Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs. PATIENTS AND METHODS: We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m(2). Seventeen patients received cyclophosphamide 600 mg/m(2), and six patients received cyclophosphamide 900 mg/m(2). Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy. RESULTS: The cyclophosphamide 900 mg/m(2) dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m(2) as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy. CONCLUSION: Pentostatin 4 mg/m(2) with cyclophosphamide 600 mg/m(2) is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.

Adult↗

PubMed2006

Hepatic veno-occlusive disease associated with immunosuppressive cyclophosphamide dosing and roxithromycin.

OBJECTIVE: To report on a patient developing hepatic veno-occlusive disease while being treated with immunosuppressive doses of cyclophosphamide (< or =2 mg/kg). CASE SUMMARY: A 66-year-old woman with autoimmune hemolytic anemia developed hepatic veno-occlusive disease while being treated with immunosuppressive cyclophosphamide 100 mg/day in combination with roxithromycin (total dose 600 mg/day). After all drugs were stopped, the patient recovered within 2 weeks. The Naranjo probability scale indicated a probable relationship between veno-occlusive disease and treatment with cyclophosphamide in this patient. DISCUSSION: Since roxithromycin inhibits CYP3A4, which is involved with cyclophosphamide metabolism, a drug-drug interaction could have been responsible. In addition, roxithromycin is an inhibitor of the drug transporter P-glycoprotein, possibly leading to accumulation of cyclophosphamide in endothelial cells. Alternatively, since cyclophosphamide has been reported to induce apoptosis, roxithromycin could have rendered endothelial cells more vulnerable for apoptosis. CONCLUSIONS: In specific patients, cyclophosphamide can be associated with hepatic veno-occlusive disease at immunosuppressive doses.

Aged↗

PubMed2000

Cyclophosphamide in the treatment of idiopathic pulmonary fibrosis: a prospective study in patients who failed to respond to corticosteroids.

STUDY OBJECTIVES: To prospectively examine the role of cyclophosphamide in patients with idiopathic pulmonary fibrosis that is unresponsive to or intolerant of high-dose steroid treatment. DESIGN: Prospective study. SETTING: Tertiary referral center. PATIENTS: Nineteen patients with biopsy specimen-proven usual interstitial pneumonia who failed to respond (n = 16) or experienced adverse effects (n = 3) from corticosteroid treatment (1 mg/kg/d for 3 months). INTERVENTION: Steroid therapy was tapered quickly, and oral cyclophosphamide, 2 mg/kg/d, was prescribed (mean duration of treatment, 6.0 +/- 0.9 months). MEASUREMENTS AND RESULTS: In 10 patients, response to therapy was determined by pretreatment and posttreatment clinical (dyspnea), radiographic (chest radiograph), and physiologic (pulmonary function, including exercise saturation) scores (CRP). Response was defined as a > 10-point drop in CRP; stable as +/- 10-point change in CRP; and nonresponders as > 10-point rise in CRP. In nine patients, physiologic criteria were used to assess response; significant changes in pulmonary function were defined as follows: total lung capacity, +/- 10% of baseline value; FVC, +/- 10% of baseline value, diffusion capacity of the lung for carbon monoxide, +/- 20% of baseline value; and resting pulse oximetry, +/- 4% of baseline value. Patients who died while receiving or shortly after discontinuing cyclophosphamide were classified as nonresponders (n = 2). Among 19 patients treated with cyclophosphamide, only 1 patient demonstrated sustained response; 7 patients remained stable and 11 deteriorated while receiving the drug. Toxicity associated with cyclophosphamide was substantial; more than two thirds of the patients developed drug-related adverse effects, and almost half discontinued the drug prematurely due to side effects. In the remaining patients, cyclophosphamide therapy was discontinued due to lack of improvement or progressive deterioration. CONCLUSIONS: Cyclophosphamide therapy is of limited efficacy in patients with idiopathic pulmonary fibrosis who fail to respond or who experience adverse effects from corticosteroid treatment, and adverse effects often complicate its use.

Adrenal Cortex Hormones↗

PubMed1998

A randomized study comparing methylprednisolone plus chlorambucil versus methylprednisolone plus cyclophosphamide in idiopathic membranous nephropathy.

To assess whether chlorambucil or cyclophosphamide may have a better therapeutic index in patients with idiopathic membranous nephropathy, we compared two regimens based on a 6-mo treatment, alternating every other month methylprednisolone with chlorambucil or methylprednisolone with cyclophosphamide. Patients with biopsy-proven membranous nephropathy and with a nephrotic syndrome were randomized to be given methylprednisolone (1 g intravenously for 3 consecutive days followed by oral methylprednisolone, 0.4 mg/kg per d for 27 d) alternated every other month either with chlorambucil (0.2 mg/kg per d for 30 d) or cyclophosphamide (2.5 mg/kg per d for 30 d). The whole treatment lasted 6 mo; 3 mo with corticosteroids and 3 mo with one cytotoxic drug. Among 87 patients followed for at least 1 yr, 36 of 44 (82%; 95% confidence interval [CI], 67.3 to 91.8%) assigned to methylprednisolone and chlorambucil entered complete or partial remission of the nephrotic syndrome, versus 40 of 43 (93%; 95% CI, 80.9 to 98.5%) assigned to methylprednisolone and cyclophosphamide (P = 0.116). Of patients who attained remission of the nephrotic syndrome, 11 of 36 in the chlorambucil group (30.5%) and 10 of 40 in the cyclophosphamide group (25%) had a relapse of the nephrotic syndrome between 6 and 30 mo. The reciprocal of plasma creatinine improved in the cohort groups followed for 1 yr for both treatment groups (P < 0.01) and remained unchanged when compared with basal values in the cohort groups followed for 2 and 3 yr. Six patients in the chlorambucil group and two in the cyclophosphamide group did not complete the treatment because of side effects. Four patients in the chlorambucil group but none in the cyclophosphamide group suffered from herpes zoster. One patient per group developed cancer. It is concluded that in nephrotic patients with idiopathic membranous nephropathy both treatments may be effective in favoring remission and in preserving renal function for at least 3 yr.

Adolescent↗

PubMed1994

The effect of DTC on humoral response restoration and thymocyte subpopulations in cyclophosphamide-immunosuppressed mice.

The effects of sodium diethyldithiocarbamate (DTC) on humoral response to SRBC and restoration of the response impaired by a single cyclophosphamide dose (200 mg/kg) were tested on mice. Moreover, the effect of DTC (20 mg/kg) on thymocyte subpopulations was tested on non-immunized mice previously treated with cyclophosphamide. It was found that DTC (20 mg/kg) administered to the immunized mice enhanced humoral response to SRBC, which was reflected in the increased number of PFC and (7S) serum hemagglutinin titer. In contrast, partial restoration of the primary humoral response after DTC injection was observed in the mice administered a single cyclophosphamide dose. The effect of DTC was stronger after 6 days following cyclophosphamide injection, i.e. at the time when spontaneous restoration of T lymphocytes begins. In addition, it was found that DTC given to non-immunized mice treated with cyclophosphamide had a modulating effect on thymocyte subpopulations. Depending on the time of exposure to cyclophosphamide, DTC either increased the percentage of CD4 thymocytes or decreased the percentage of CD8, which subsequently led increased CD4/CD8 coefficient. DTC did not change the suppressing action of cyclophosphamide on the percentage of double-positive thymocytes.

Animals↗

PubMed2006

Cyclophosphamide mobilization does not improve outcome in patients receiving stem cell transplantation for multiple myeloma.

PURPOSE: Patients with multiple myeloma who undergo autologous stem cell transplantation (ASCT) and exhibit a complete response (CR) have a superior overall survival and time to progression (TTP). High-dose cyclophosphamide is often used before ASCT for mobilization of hematopoietic stem cells. We hypothesized that cyclophosphamide might further improve CR rates in patients undergoing ASCT. We searched the Mayo Clinic myeloma transplantation database for patients who had stem cell mobilization with hematopoietic growth factor alone or cyclophosphamide and growth factor. The impact of cyclophosphamide on CR rates and TTP was evaluated. PATIENTS AND METHODS: A cohort of 201 patients was identified: 127 mobilized with cyclophosphamide and growth factor and 74 with growth factor alone. There were no statistically significant differences between the 2 cohorts in regard to age, sex, b2-microglobulin level, plasma cell labeling index, cytogenetics, conditioning regimen, or disease status at time of transplantation. RESULTS: Complete response rates were 37.4% and 41.3% (P = 0.6115) for patients mobilized with cyclophosphamide combined with growth factor and growth factor alone, respectively, and TTPs were 19.9 months and 20.9 months (P = 0.59). In a multivariate analysis for TTP, cytogenetics and CR rates were the only independent variables (P = 0.0012 and P < 0.0001, respectively). CONCLUSION: We conclude that high-dose cyclophosphamide does not increase overall CR rates or improve TTP for patients with myeloma undergoing ASCT.

Adult↗

PubMed1994

Preserving renal function in patients with membranous nephropathy: daily oral chlorambucil compared with intermittent monthly pulses of cyclophosphamide.

OBJECTIVE: To compare oral chlorambucil and intravenous cyclophosphamide-based drug regimens in the treatment of patients with membranous nephropathy and deteriorating renal function. DESIGN: Randomized study. SETTING: University hospital and teaching hospitals. PATIENTS: 18 patients with membranous nephropathy, a nephrotic syndrome, and deteriorating renal function. INTERVENTION: Chlorambucil (0.15 mg/kg body weight per day orally in months 2, 4, and 6) and prednisone (three intravenous pulses of 1 g of methylprednisolone followed by oral prednisone at 0.5 mg/kg per day in months 1, 3, and 5) or intravenous cyclophosphamide (750 mg/m2 body surface area once every month for 6 months) and methylprednisolone (three intravenous 1-g pulses in months 1, 3, and 5). MEASUREMENTS: Serum creatinine, serum cholesterol, serum albumin, and urinary protein levels. RESULTS: Before treatment, no statistical differences were found between the treatment groups. Six months after treatment was started, serum creatinine levels had decreased in the group treated with chlorambucil, methylprednisolone, and prednisone from a mean of 260 +/- 112 mumol/L to 186 +/- 74 mumol/L (P = 0.003) and had increased in the group treated with intravenous cyclophosphamide and methylprednisolone from 218 +/- 85 mumol/L to 297 +/- 143 mumol/L (P = 0.02; difference between both groups, P < 0.001). Serum albumin levels increased in both groups by 9 and 6 g/L, respectively, and the urinary protein/creatinine ratio decreased by 2.6 and 3.1 g/10 mmol, respectively. At the end of follow-up (median, 15 months; range, 6 to 36 months), one patient in the chlorambucil group and four patients in the cyclophosphamide group had reached end-stage renal failure after 36, 12, 12, 18, and 18 months of therapy, respectively. One patient in the intravenous cyclophosphamide group died after 6 months of therapy. CONCLUSIONS: Thus far, both oral chlorambucil and oral cyclophosphamide have been shown to be effective in the treatment of patients with membranous nephropathy and deteriorating renal function. Our study shows that intermittent monthly pulses of low-dose cyclophosphamide are ineffective in preserving renal function in such patients.

Administration, Oral↗

PubMed1976

[Cytogenetic effect of cyclophosphamide in a culture of human lymphocytes following its activation in the bodies of mice].

Cytogenetic effect of cyclophosphamide in cultured human lymphocytes after its activation in C57BL/6 mice in vivo was investigated. Cyclophosphamide was injected intraperitoneally in mice for 30 min. at doses of 200, 400, 600, 800 and 1000 mg/kg. Blood serum with activated metabolites of cyclophosphamide was added to human lymphocyte culture. The dependence of the part of aberrant metaphases on the concentration of cyclophosphamide after the activation can be presented as equation rho==1-e-(KC+alpha)2 and the total number of breaks as X=e(KC+alpha)2-1, where rho is a part of aberrant metaphases, X is a number of breaks of chromosomes per cell, C is the concentration, K and alpha are coefficients. The part of chromatid breaks from the total number of chromosome damages is constant for all concentrations and the comprises on the average 79,11%. Only the chromatid type of exchanges are observed. Distribution of chromosome breaks in cells corresponds to geometrical, but not to Poisson's distribution. Cyclophosphamide belongs to the group of one-sited mutagens in its cytogenetic chatacteristics. The alkylating activity of cyclophosphamide metabolites, estimated by means of NBP test, increases up to the dose 400 mg/kg and then remains constant for the strain of mice studied, cytogenetic activity increasing. Cyclophosphamide does not produce cytogenetic activity without activation. To test chemical substances for mutagenic activity, it is suggested to activate them in the mouse organism with the following administrating blood serum of these animals with the metabolites of tested (or with primary) substances in the study of their mutagenic activity on human lymphocyte culture.

Animals↗

PubMed1999

Chemopreventive doses of amifostine confer no cytoprotection to tumor nodules growing in the lungs of mice treated with cyclophosphamide.

In addition to the cytoprotective benefits of amifostine (Ethyol; Alza Pharmaceuticals, Palo Alto, CA/US Bioscience, West Conshohocken, PA) to normal cells, it also prevents the induction of somatic mutations that can lead to therapy-induced second cancers. The mutagenic effects of cyclophosphamide, an agent that is known to be mutagenic to normal cells, were determined in mouse splenocytes using a mutational assay system. Cyclophosphamide 100 mg/kg increased mutant frequencies 10-fold. In contrast, amifostine 100 mg/kg, whether administered 30 minutes before or 2 hours after cyclophosphamide administration, resulted in eightfold lowered mutant frequencies. To address potential cytoprotective effects on tumors exposed to this dose, amifostine was administered to tumor-bearing mice either 30 minutes before or 2 hours after the administration of cyclophosphamide. Cyclophosphamide (range, 10 to 100 mg/kg) was administered intraperitoneally into mice 4 days following the injection of 3.5 x 10(5) viable fibrosarcoma (FSa) cells. At this time, microcolonies of FSa tumors containing 50 to 200 cells were present in the lung. The number of FSa lung nodules formed at the end of 14 days in control animals was compared with that of animals treated with cyclophosphamide +/- amifostine. No cytoprotection of murine FSa tumors by amifostine was observed across the entire cyclophosphamide dose range tested, regardless of time of administration, demonstrating the utility of amifostine as a chemopreventive drug under conditions that do not allow cytoprotection for tumor cells.

Amifostine↗

PubMed2005

Reduced radiosensitivity and increased CD40 expression in cyclophosphamide-resistant subclones established from human cervical squamous cell carcinoma cells.

To investigate the interaction between anticancer drug resistance and radioresistance in cervical cancer cells, 3 single cell-derived cyclophosphamide-resistant subclones were established from the drug- and radiosensitive human cervical squamous cell carcinoma cell line ME180 by chronic exposure cultures with 4-hydroxy-cyclophosphamide followed by limiting dilution. The established cyclophosphamide-resistant subclones were also radio- and multidrug-resistant to 7 other anticancer drugs. Flow cytometric analysis revealed significantly increased levels of CD40 expression on the 3 resistant subclones, whereas no CD40 expression was found on the parent ME180 cells. However, there were no changes in the expression levels of CD29, CD49a-CD49f or CD59 between the parent cells and resistant subclones. A recombinant human soluble CD40 ligand had no effect on the proliferation of the resistant subclones. Irradiation had no effect on the 4-hydroxy-cyclophosphamide sensitivity of the parent cells. These results indicate that the established cyclophosphamide-resistant subclones have impaired cell death signals, which are common to both drug- and radiation-induced apoptosis, and cyclophosphamide may not be an adequate drug for use in concurrent chemoradiotherapy. Furthermore, CD40 activation signals may be associated with the multidrug- and radioresistance in these cyclophosphamide-resistant subclones.

Antineoplastic Agents↗

PubMed1991

Administration of IL-7 to mice with cyclophosphamide-induced lymphopenia accelerates lymphocyte repopulation.

Lymphopenia was induced in mice by a single injection of cyclophosphamide. IL-7 or a control protein were administered to the mice twice daily and the cellularity and composition of the spleen, lymph node, bone marrow, and thymus were determined at various time points thereafter. In comparison to the control cyclophosphamide-treated mice, animals receiving cyclophosphamide and IL-7 had an accelerated regeneration of splenic and lymph node cellularity. There was no significant difference in the rate of recovery of the bone marrow and thymus of the control and IL-7-treated mice. Assessment of the pre-B cell compartment revealed a dramatic increase in total pre-B cell numbers in the spleen and bone marrow of the IL-7-treated mice as measured by both flow microfluorimetry and a pre-B cell colony-forming assay. This was followed in a few days by a significant increase in surface IgM+B cell numbers to levels above normal values in both the spleen and lymph node. IL-7 administration to cyclophosphamide-treated mice also resulted in an accelerated recovery of peripheral CD4+ and CD8+ cell numbers in the spleen and lymph node. The numbers of CD8+ cells were increased by twofold over normal levels in cyclophosphamide-treated mice receiving IL-7. Myeloid recovery was determined in cyclophosphamide treated mice by assessing the numbers of CFU-granulocyte-macrophage and Mac 1+ cells. There was no significant difference in myeloid recovery between cyclophosphamide-treated mice receiving IL-7 or control protein. These results suggest that administration of IL-7 after chemical-induced lymphopenia may have therapeutic benefits in shortening the period required to achieve normal lymphoid cellularity.

Animals↗

PubMed1989

A limited sampling strategy for cyclophosphamide pharmacokinetics.

A limited sampling strategy was developed to estimate the total area under the curve of plasma cyclophosphamide concentrations versus time (AUC). The strategy was developed with a training set consisting of 29 pharmacokinetic studies in 16 patients who received 1-h i.v. infusions of cyclophosphamide at a dosage of 1000 mg/m2. The strategy was developed by applying stepwise forward multiple regression analysis to cyclophosphamide concentrations observed at each time in the training set (independent variables) versus the AUC (dependent variable). It was confirmed by applying stepwise backward elimination regression analysis to the same data set. The final sampling strategy, which utilized three time points, was: AUC = 40.18C24 + 8.79C4 + 0.83C1 - 28 (dosage/1000), where C24, C4, and C1 represent plasma cyclophosphamide concentrations at 24, 4, and 1 h, respectively, and the dosage is in mg/m2 (r = 0.98). The strategy was validated prospectively with a test data set consisting of 14 pharmacokinetic studies in 11 patients who received 1-h i.v. infusions of cyclophosphamide at dosages of 300, 600, or 1200 mg/m2. The strategy proved highly predictive, with correlation coefficient between predicted and actual AUC of 0.94. The strategy also proved unbiased, with mean percentage of error (+/- SE) of 3.3 +/- 3.6%, and precise, with mean absolute percentage of error of 9.3 +/- 2.7%. The sampling strategy developed is being used in a multiinstitution trial of cyclophosphamide in an effort to relate cyclophosphamide pharmacokinetics, as expressed by AUC, with the toxic or therapeutic pharmacodynamic responses of the drug.

Cyclophosphamide↗

PubMed1987

Enhancement of natural killer-cell activity in young and old mice treated with cyclophosphamide on a circadian basis.

Several recent studies have revealed a significant circadian variation in immunological functions including natural killer (NK)-cell activity against tumor target cells both in rodents and in man. We have previously reported circadian changes in antibody-forming cells as well as NK-cell activity in mice and rats. The present study was undertaken to determine the effect of high and low doses of cyclophosphamide on circadian NK-cell activity in young (8-week-old) and old (8-month-old) female C57BL/6 (B/6) mice. The results revealed that, in general, young animals had higher NK activity than old animals. In both young and old mice, the high dose of cyclophosphamide depressed NK activity. In contrast, the low dose of cyclophosphamide showed significantly increased NK activity, which was proportionately greater in old mice than in young mice. Cyclophosphamide-enhanced NK activity was found to be higher during the resting period than during periods of activity. Apparently, high NK activity can be induced with a circadian-based immunotherapy regime using low-dose cyclophosphamide in both young and old animals. It is presently not clear if increased NK activity caused by cyclophosphamide is due to a decrease in activity of immunoregulatory cells, such as T cells, B cells, or macrophages. More studies are required to determine the basis of increased NK activity caused by treatment with low dosages of cyclophosphamide in mice.

Age Factors↗

PubMed1984

Moderate to high dose cyclophosphamide and intercalated Corynebacterium parvum in patients with metastatic lung cancer.

Thirty-nine patients with histologically proven widely metastatic bronchogenic carcinoma were treated with cyclophosphamide and Corynebacterium parvum. The dosage of cyclophosphamide was higher than conventional as previous work had indicated better results with increased dosage. Experimental work had suggested that the addition of Corynebacterium parvum would increase the antitumour effect and possibly reduce the cyclophosphamide induced granulocytopenia. A short treatment programme using three i.v. injections of cyclophosphamide, 1.5 g/m2, 2.5 g/m2 then 3.5 g/m2, at 3 week intervals were given. Four days after each cyclophosphamide injection, C. parvum 2 mg/m2 i.v. was administered. An overall 38% tumour response rate was observed, 18% for patients with non-small-cell carcinoma and 65% for small-cell carcinoma patients. The median survival for the 39 patients was 5 months (range 1-16+ months). These results, particularly for the non-small-cell patient group are comparable to those obtained with intensive combination chemotherapy regimens administered intermittently over much longer periods. An important consideration, objectively assessed in the present study, was the effect of treatment on quality of life and breathlessness. Improvement was noted not only in those patients with tumour response but also in a proportion of those who did not fulfil the criteria of response. Toxicity was also carefully assessed and, although the cyclophosphamide dosages were higher than conventionally used, no undue problems were noted. The addition of C. parvum did not have any noticeable beneficial effect. Cyclophosphamide given at dosages higher than is usual but which do not require bone marrow rescue is worthy of further study.

Adult↗

PubMed1984

Plasma concentrations of 4-hydroxycyclophosphamide and phosphoramide mustard in patients repeatedly given high doses of cyclophosphamide in preparation for bone marrow transplantation.

Plasma half-life and area under the curve (AUC) values for cyclophosphamide were determined in patients given this agent iv at doses of 50-60 mg/kg/infusion. Apparent plasma half-life and AUC values for the metabolites 4-hydroxycyclophosphamide and phosphoramide mustard were also determined in some of these patients. Disappearance from the plasma of the parent compound as well as that of the metabolites was approximately first-order. Plasma half-life values for cyclophosphamide ranged from 45 to 480 mins; AUC values ranged from 10 to 188 mM X min. As expected, AUC values for cyclophosphamide increased approximately linearly with an increase in its plasma half-life. Apparent plasma half-life values for 4-hydroxycyclophosphamide and phosphoramide mustard increased approximately linearly with an increase in plasma half-life values for cyclophosphamide; the slopes of these relationships were 1.35 and 1.97, respectively, but did not quite extrapolate to zero. AUC values for 4-hydroxycyclophosphamide and phosphoramide mustard remained approximately constant at about 5 and 15 mM X min, respectively, over the relatively wide range of plasma half-life and AUC values obtained for cyclophosphamide. On the basis of these observations we suggest that (a) changes in the rate of cyclophosphamide hydroxylation, effected by whatever means, will not alter the systemic therapeutic and toxic responses to a given dose of cyclophosphamide, given that the cytotoxic effects of this agent are directly proportional to AUC values of 4-hydroxycyclophosphamide and/or phosphoramide mustard, and (b) in most cases, 4-hydroxycyclophosphamide, and not phosphoramide mustard, is likely to be the circulating metabolite of therapeutic importance in humans since the AUC values for phosphoramide mustard exceeded those for 4-hydroxycyclophosphamide by only a factor of 3 and tumor and bone marrow cells proliferating in culture are generally substantially (8-25-fold) more sensitive to 4-hydroxycyclophosphamide.

Adolescent↗

PubMed1984

Accumulation and persistence of cyclophosphamide-induced sister chromatid exchange in murine peripheral blood lymphocytes.

Sister chromatid exchange (SCE) responses were evaluated in lipopolysaccharide-stimulated murine peripheral blood lymphocytes assayed at various times following single or multiple injections of cyclophosphamide (3 mg/kg). Following a single injection, SCE levels in cultured lymphocytes from blood sampled at 5 min, 20 min, 35 min, 1 hr, and 3 hr postexposure were 17.1 +/- 2.0 (S.D.), 19.9 +/- 3.0, 19.3 +/- 1.8, 21.6 +/- 2.4, and 20.6 +/- 2.3, respectively. The control base-line SCE frequency was 11.2 +/- 1.2. The rapid initial increase in SCEs is consistent with the rapid increase reported previously in circulating active metabolites in rats following cyclophosphamide treatment. In peripheral blood lymphocytes cultured at 1 and 24 hr after serial injections of cyclophosphamide (3.0 mg/kg) two, four, and six times (every other day), a dose-related accumulation of SCEs occurred. Accumulation of SCEs was also observed in lymphocytes cultured at 24 and 72 hr following 12 multiple injections (three times weekly) of cyclophosphamide (3 mg/kg) (24.8 +/- 1.5 and 17.6 +/- 1.4, respectively) as compared to the single-injection group assayed at 24 and 72 hr postexposure (16.0 +/- 2.4 and 12.9 +/- 1.4, respectively). In the 12-multiple-injection study, an initial rapid decline at 72 hr was followed by a gradual decrease in SCE levels (1 week, 16.9 +/- 1.3; 2 weeks, 15.2 +/- 0.7; and 4 weeks, 13.4 +/- 1.1) which returned to near base-line (11.2 +/- 0.9) levels at 8 weeks. In the 12-multiple-injection study, successful growth of parallel concanavalin A-stimulated cultures was achieved only at 1, 2, and 4 weeks postexposure. Elevated SCE frequencies were observed at these intervals (16.2 +/- 2.1; 16.7 +/- 0.9; 14.2 +/- 0.3, respectively) relative to base-line SCE levels in concanavalin A-stimulated cells (12.1 +/- 1.8). The observed accumulation of SCEs with repeated exposure and persistence of SCE-inducing lesions parallel human data reported previously. The maximum induced (total minus baseline) SCE levels (10.2) observed in cultured lipopolysaccharide-stimulated lymphocytes from blood sampled at 1 hr after a single 3.0-mg/kg injection of cyclophosphamide were comparable or slightly higher than those (7.1) produced by the same dose of cyclophosphamide in murine bone marrow cells labeled with BrdUrd in vivo. However, in contrast to lymphocytes, bone marrow and alveolar macrophage cells did not accumulate SCEs upon repeated cyclophosphamide treatments.

Animals↗

PubMed1984

Effect of cyclophosphamide on survival of mice and incidence of metastatic tumor following intravenous and intracardial inoculation of tumor cells.

We studied the effect of cyclophosphamide on survival of mice and the incidence of tumor implants in various organs following both i.v. and intraarterial dissemination of tumor cells. Female C3H/HeN mice received cyclophosphamide (240 mg/kg) i.p. 4 days prior to inoculation of various doses of KHT tumor cells. Mice were followed to death, and the amount of tumor present was roughly quantified. Following i.v. inoculation of tumor cells, survival was decreased in cyclophosphamide-treated mice compared to control mice. However, survival was not affected by treatment with cyclophosphamide in mice receiving intracardial tumor cell injections. Pretreatment with cyclophosphamide caused a dramatic increase in the number of lung tumor implants following both routes of tumor cell administration. A similar tumor-promoting effect by cyclophosphamide could not be documented in the brain, heart, kidney, adrenal, or ovary. The study suggests that cyclophosphamide has a much greater effect on ultimate deposition and growth of tumor implants in the lungs than in other systemic organs or in the central nervous system.

Animals↗