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PubMedDate not supplied

Adriamycin, cyclophosphamide and vindesine (ACV) versus mitoxantrone, cyclophosphamide and vindesine (NCV) in advanced breast cancer.

The choice of chemotherapy for advanced breast cancer patients is based on both response rates and anticipated side effects. Two polychemotherapy regimens, ACV and NCV, were compared in an open study with 90 patients of whom 69 were evaluable both for efficacy and toxicity. Both ACV and NCV are active in metastatic breast cancer. ACV leads to more remissions in a relatively short time. NCV treatment results in a larger proportion of stable diseases. ACV causes more important alopecia, nausea and vomiting. NCV gives more anemia. The characteristics of both treatment results give the oncologist the opportunity to choose in particular clinical situations.

Adult↗
PubMed1998

[Comparison of adjuvant chemotherapy in breast carcinoma with a combination of cyclophosphamide, methotrexate, 5-fluorouracil (CMF) and AC (doxorubicin, cyclophosphamide). Initial results of a national cooperative study].

The aim of this multicentric, prospective randomized trial is to evaluate and to compare, effects and toxicities of two chemotherapeutic combinations (AC and CMF) in adjuvant treatment of breast cancer. Both combinations were given in equitoxic doses and number of cycles was only four. There are 106 women treated for breast cancer T1c-3a, N0-1, M0 in the study. After surgery the patients were randomized, 54 for AC combination and 52 for CMF. We evaluate toxicity of this treatment in all patients in the study. Hematological and nonhematological side effects were comparable in both groups except alopecia (in the group AC was 100%). The study is not finished yet. Preliminary analysis does not show any difference between these two groups.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2006

Mechanisms of venoocclusive disease resulting from the combination of cyclophosphamide and roxithromycin.

BACKGROUND: High doses (>or=500 mg/m) of cyclophosphamide are known to cause venoocclusive disease (VOD). The authors recently observed a patient treated with immunosuppressive cyclophosphamide doses (100 mg/day) and roxithromycin who developed VOD. Because roxithromycin inhibits cytochrome P450 (CYP) 3A4 and P-glycoprotein, the patient may have been exposed to higher cyclophosphamide and/or cyclophosphamide metabolite concentrations. METHODS: The effect of roxithromycin on the metabolism and toxicity of cyclophosphamide was studied using human hepatic microsomes and a human endothelial cell line. RESULTS: Cyclophosphamide or roxithromycin at concentrations from 0.05 to 500 micromol/L were not toxic to endothelial cells as assessed by lactate dehydrogenase (LDH) leakage assay. However, the combination of roxithromycin (500 micromol/L) and cyclophosphamide was toxic for all the tested cyclophosphamide concentrations (0.05 to 500 micromol/L) without clear concentration dependence (LDH ratio 38.3 +/- 11.0 [mean +/- SEM] for the combination with cyclophosphamide 0.05 micromol/L and 50.2 +/- 10.2 for the combination with cyclophosphamide 500 micromol/L; P <or= 0.005 for all tested combinations vs. control). Although roxithromycin did not favor the generation of toxic metabolites from cyclophosphamide, it led to cyclophosphamide accumulation due to inhibition of both CYP3A4 and CYP2B6. Although roxithromycin inhibited P-glycoprotein, this was not the mechanism by which cyclophosphamide toxicity was increased because cyclophosphamide in combination with other P-glycoprotein inhibitors was not toxic to endothelial cells. In the presence of roxithromycin (500 micromol/L), cyclophosphamide (500 micromol/L) induced apoptosis in endothelial cells (34.3 +/- 10.4% apoptotic cells [in % of total cells] for the combination of cyclophosphamide and roxithromycin, 0.7 +/- 0.25% for cyclophosphamide alone, 0% for roxithromycin alone; P < 0.0001) most probably by mitochondrial membrane permeability transition and release of cytochrome c. CONCLUSIONS: The combination cyclophosphamide and roxithromycin, but not the individual compounds, is toxic to endothelial cells by inducing apoptosis. Inhibition of P-glycoprotein and formation of toxic metabolites are unlikely causes.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Nonlinear pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide in patients with metastatic breast cancer receiving high-dose chemotherapy followed by autologous bone marrow transplantation.

The pharmacokinetics of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide has been evaluated in 12 patients with metastatic breast cancer undergoing high-dose chemotherapy followed by bone marrow transplantation. Each patient received an initial dose of 4 g/m2 of cyclophosphamide over 90 min to prime peripheral blood progenitor cells (the first course), and 3 weeks later, 6 g/m2 of cyclophosphamide with 800 mg/m2 of thiotepa by 96-hr infusion before marrow stem cell infusion (the second course). Whole blood cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide concentrations were measured by a GC-EIMS method using deuterium labeled compounds as internal standards. In addition, plasma and urine cyclophosphamide concentrations were determined by a GC assay. Whole blood concentrations of cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide vs. time data and urinary excretion of cyclophosphamide data from the first course were co-modeled using a one-compartment model with Michaelis-Menten saturable elimination in parallel with first-order renal elimination (N = 7) or first-order metabolic and renal elimination (N = 5) for cyclophosphamide and one-compartment model with first-order elimination for 4-hydroxycyclophosphamide/aldophosphamide. The parallelism between cyclophosphamide and 4-hydroxycyclophosphamide/aldophosphamide disposition curves implies that the pharmacokinetics of 4-hydroxycyclophosphamide/aldophosphamide is formation limited; only the fractional 4-hydroxycyclophosphamide/ aldophosphamide clearance rate (Clmet/Fmet) can be estimated. The mean Vmax and Km for cyclophosphamide were 0.78 microM/min and 247 microM, respectively. The mean nonrenal clearance (Clnr) of cyclophosphamide for five patients with apparent first-order elimination of cyclophosphamide was 67 ml/min. The mean Clmet/Fmet of 4-hydroxycyclophosphamide/aldophosphamide was 2982 ml/min. The mean renal clearance (Clr) of cyclophosphamide was 29 ml/min and 24 ml/min for the first course and the second course, respectively. The correlations between cyclophosphamide AUCs and 4-hydroxycyclophosphamide/aldophosphamide AUCs were sought for both drug courses. Blood and plasma cyclophosphamide concentrations were remarkably similar, indicating that cyclophosphamide partitions equally in the red cell and plasma volume. Computer simulation of the effect of potential alterations in Michaelis-Menten saturable elimination and renal clearance on 4-hydroxycyclophosphamide/aldophosphamide has been used to illustrate the complex relationship between the exposure to parent compound and active metabolite.

Adult↗
PubMed2000

Cyclophosphamide inhibits the development of diabetes in the diabetes-prone BB rat.

AIMS/HYPOTHESIS: Cyclophosphamide has been shown to augment the diabetic process in NOD mouse and BB rat models of Type I (insulin-dependent) diabetes mellitus. Because cyclophosphamide has, however, been shown to increase immunoregulatory cell activity, we examined if cyclophosphamide treatment increases immunoregulatory cell activity and inhibits the diabetic process in BB rats. METHODS: The development of insulitis and diabetes was explored in BB rats treated with saline and cyclophosphamide (60 to 175 mg/kg body weight). Subsets of spleen cells were assessed by flow cytometry and cytokine gene expression by RT-PCR. To determine if cyclophosphamide induces immunoregulatory cell activity, the development of diabetes was assessed in BB rats injected with spleen cells from rats treated with saline and cyclophosphamide. RESULTS: All dosages of cyclophosphamide decreased the development of diabetes. The degree of insulitis was lower in pancreata from 55-day-old rats treated with cyclophosphamide than those from controls. Cyclophosphamide caused no alterations in the numbers of NK cells, T-cell subsets, or RT6.1+ T cells. The adoptive transfer of spleen cells from cyclophosphamide-treated rats to BB rats inhibited the development of diabetes. Cyclophosphamide treatment decreased IL-12, IL-1beta, IL-2, IFN-gamma and TNF-alpha gene expressions in mononuclear spleen cells but IL-4 gene expression increased. CONCLUSION/INTERPRETATION: These findings show that cyclophosphamide treatment decreases the development of diabetes by inhibiting the development of insulitis. This inhibitory action of cyclophosphamide on the diabetic process seems to be mediated by the induction of immunoregulatory cell activity. The suppression of cytokines that promote Thl cell differentiation by cyclophosphamide treatment could also play a part in the diabetes sparing effect of cyclophosphamide.

Aging↗
PubMed2003

Risk factors for sterile hemorrhagic cystitis in dogs with lymphoma receiving cyclophosphamide with or without concurrent administration of furosemide: 216 cases (1990-1996).

OBJECTIVES: To determine incidence and identify predisposing factors for sterile hemorrhagic cystitis (SHC) in dogs with lymphoma that were treated with cyclophosphamide and to evaluate whether furosemide administered i.v. concurrently with cyclophosphamide decreased the incidence of SHC. DESIGN: Retrospective study. ANIMALS: 216 dogs with lymphoma. PROCEDURE: Medical records of dogs with lymphoma that received cyclophosphamide chemotherapy in accordance with 1 of 2 protocols, with or without concurrent i.v. administration of furosemide, were examined. Data for the 2 groups were analyzed to determine the incidence and predisposing factors (age, breed, sex, weight, previous or preexisting disease, previous or preexisting urinary tract infection, neutropenia, azotemia, dose, and number of cyclophosphamide treatments) for cyclophosphamide-associated SHC. RESULTS: Cyclophosphamide-associated SHC developed in 12 of 133 (9%) dogs that had not received concurrent administration of furosemide and cyclophosphamide treatments; of the 83 dogs that had received furosemide, only 1 (1.2%) developed SHC. Dogs receiving cyclophosphamide and furosemide concurrently were significantly less likely to develop SHC than dogs that did not receive furosemide. Dogs with previous or preexisting immune-mediated disease were significantly more likely to develop cyclophosphamide-associated SHC. CONCLUSIONS AND CLINICAL RELEVANCE: Analysis of results suggested an association between i.v. administration of furosemide concurrently with cyclophosphamide and decreased incidence of cyclophosphamide-associated SHC. Incidence of cyclophosphamide-associated SHC was similar in treated dogs that did not receive concurrent furosemide to that observed for other studies in which cyclophosphamide was administered orally. Cyclophosphamide-associated SHC appeared to develop early during the course of chemotherapy when furosemide was not administered concurrently with cyclophosphamide.

Animals↗
PubMed2002

[Comparison of various cyclophosphamide treatment regimens on the course and outcome of lupus nephritis ].

INTRODUCTION: Immunosuppressive drugs, particularly cyclophosphamide, are widely accepted as the treatment of choice for severe, proliferative lupus nephritis. However, there is no consensus with regard to: 1) the dose required for achieving control of disease activity; 2) duration of cyclophosphamide therapy after the achievement of treatment response; 3) treatment of lupus nephritis relapses [1-5]. In the Institute of Rheumatology, Belgrade, two regimens of intravenous cyclophosphamide have been introduced in the treatment of lupus nephritis patients years ago. The first has comprised the so called "small pulses" that have been used since 1985, and the second has been standard protocol with high doses of cyclophosphamide, accepted in 1990. Results of these follow-up studies were published previously [6-8]. AIM: The aim of this study was to compare the efficacy of two regimens of intravenous pulse cyclophosphamide in the treatment of patients with severe lupus nephritis. METHODS: We analyzed the results of two follow-up studies comprising patients with lupus nephritis, treated with cyclophosphamide: 1) 41 females treated with "small pulses", consisting of 400 mg of cyclophosphamide weekly at treatment onset, followed by the same dose fortnightly for the next three months, and finally on monthly basis for several months or years; 2) 33 patients (29 females and 4 males) treated with standard protocol consisting of "induction phase" with 6 monthly pulses of high doses (0.5-0.75 g/m2 body surface), followed by "maintenance phase" with quarterly pulses for additional 1-2 years. The evaluation of long-term treatment effects was based on remission/response rate [9], number of patients with renal failure, end-stage renal disease and death outcome. RESULTS: Groups of patients were quite comparable with respect to their demographic and clinical data (Table 1). The only difference was much higher frequency of renal biopsy in "high dose" cyclophosphamide pulse (85% versus 32%), confirming the presence of proliferative lupus nephritis. Cummulative dose of cyclophosphamide and treatment duration were not significantly different between treatment groups. At the end of the follow-up, distributions of favorable (remission/response) and unfavorable outcome was similar (p = 0.831; Mann-Whitney U test), as well as dynamics of remission achieving (p = 0.068; Log-rank test), cummulative renal survival (p = 0.129; Log-rank test) and patient survival (p = 0.577; Log-rank test). DISCUSSION: Similar efficacy of two different cyclophosphamide regimens in our patients with lupus nephritis was not surprising considering that cummulative cyclophosphamide doses and treatment duration were similar obtaining similar control of disease. During induction phase of treatment, patients on small pulses have received even higher cummulative dose of cyclophosphamide. Aggressive immunosuppressive treatment with cyclophosphamide has significantly ameliorated the outcome of lupus nephritis. In different studies, rate of assessed clinical response is 60-80 [13-17]. Significant proportion (42%) of patients who achieved partial remission, as well as complete remission, developed flare of renal disease several months after the end of the treatment, necessitating restarting of pulse cyclophosphamide therapy. The results of our study were in accordance with those results, especially with results of Mosca et al. [18] who have applied the duration of treatment similar to ours in high pulse regimen. CONCLUSION: Treatment response did not differ between two different cyclophosphamide regimens (small pulses and standard high doses protocol), but standard protocol seemed to be more comfortable for patients. We recommend standard protocol for patients with biopsy proved proliferative lupus nephritis as a gold treatment standard. However, sustained remission of proliferative lupus nephritis is a goal that still remains to be achieved.

Adolescent↗