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PubMed1992

Suppressing effects of glucan on micronuclei induced by cyclophosphamide in mice.

The effect of pretreatment with carboxymethylglucan (CMG) on the frequency of micronuclei induced by cyclophosphamide administration in mice was evaluated. Two doses of CMG (50 mg/kg body weight) injected either intraperitoneally 24 h or intravenously 1 h prior to two cyclophosphamide administrations (80 mg/kg) significantly decreased the frequency of micronucleated PCE in bone marrow. Of two evaluated derivatives of carboxymethylglucan, the K3 derivative was most efficient. The results show that it is possible to achieve a suppressive effect of soluble carboxymethylglucan prepared from Saccharomyces cerevisiae against cyclophosphamide mutagenicity. The notion may be useful for glucan's effects against pharmacocarcinogenesis. Therapeutic application of glucan with cyclophosphamide therapy may provide a remarkable decrease of the secondary tumour risk. The utilization of these results for human patients needs to be considered.

Animals↗

PubMed1995

Effect of carboxymethyl-chitin-glucan on cyclophosphamide induced mutagenicity.

The effect of high molecular carboxymethyl-chitin-glucan (CMCG), administered either intraperitoneally, intravenously or orally prior to cyclophosphamide injection, on the frequency of micronucleated reticulocytes was evaluated in peripheral blood of female ICR mice. Both intraperitoneal and intravenous administration of CMCG decreased the clastogenic effect of cyclophosphamide. The protective effect of CMCG was concentration dependent, with a higher decrease achieved by 100 mg/kg than by 50 mg/kg body weight. On the other hand, not even five peroral pretreatments with CMCG in the dose of 200 mg/kg body weight during the week prior to simultaneous administration of CMCG and cyclophosphamide induced a decrease of micronucleated reticulocytes in peripheral blood. It is therefore conceivable that CMCG failed to pass through the gastrointestinal tract, probably due to its high molecular weight. The antimutagenic effect of CMCG against cyclophosphamide was manifested by its intraperitoneal and intravenous administration to female ICR mice.

Animals↗

PubMed1983

Moderate-dose cyclophosphamide for disseminated ovarian carcinoma: a phase II study.

Fifty-six evaluable patients with advanced ovarian carcinoma (FIGO III or IV), without prior cytotoxic chemotherapy, were studied to assess the activity of single-agent moderate-dose cyclophosphamide, 40 mg/kg to a maximum dose of 3000 mg, given intravenously as a bolus injection every 3 weeks. All patients were treated as outpatients. Moderate-dose cyclophosphamide resulted in 36 (64%) objective responses (19 CR, 17 PR). Nausea and severe vomiting occurred in all patients, but no patient needed hospitalization for this complication. Other side-effects observed were alopecia (100%), leukocytes less than or equal to 2500/microliters (18%), chemical cystitis (11%) and sepsis (4%). The median duration of response was 11 months, and the estimated median survival by the life-table method for responders was 16 months and for non-responders 4 months (P less than 0.001). Clinical trials previously performed by our group comparing cyclophosphamide alone, either vs cis-platinum, adriamycin and hexamethylmelamine or vs Hexa-CAF, showed a better remission rate with the use of moderate-dose cyclophosphamide alone. Therefore we suggest further investigation of this agent in a moderate dose in disseminated ovarian carcinoma.

Adult↗

PubMed1988

Comparative toxicity of cisplatin, carboplatin (CBDCA) and iproplatin (CHIP) in combination with cyclophosphamide in patients with advanced epithelial ovarian cancer.

Sixty patients with FIGO stage IIb, IIc, III and IV ovarian cancer were entered into a randomized Phase III study of cyclophosphamide 600 mg/m2 with cisplatin 100 mg/m2, iproplatin 240 mg/m2 or carboplatin 300 mg/m2. Dose modifications were made according to renal function and myelotoxicity. The arms containing carboplatin (CBDCA) and iproplatin (CHIP) were not shown to be significantly different from the cisplatin containing arm with regard to response rate, duration of response and survival. Subjective toxicity showed that cisplatin and cyclophosphamide therapy was associated with more nausea and vomiting (P = 0.0005). The duration of vomiting showed a significant increase with successive courses of chemotherapy for the cisplatin containing arm only (P less than 0.003). The cyclophosphamide/CHIP combination caused significantly more diarrhoea (P less than 0.0006). Alopecia was more severe (P less than 0.02), and neurotoxicity was more common, in patients who received cyclophosphamide and cisplatin (paraesthesiae P = 0.0007, tinnitus P less than 0.00005, deafness P = 0.0018). All three combinations caused cumulative toxicity on haemoglobin (Hb) (P less than 0.001 for each treatment), leukocyte count (WCC) (P less than 0.0005 for each treatment), and platelet count (P less than 0.0005 for each treatment). The degree of fall in Hb for each course of therapy was greater in the cisplatin containing arm compared with the CHIP and CBDCA arms which were not significantly different from each other (P = 0.0005). For WCC the cisplatin/cyclophosphamide regimen was significantly less toxic than CHIP/cyclophosphamide, with CBDCA/cyclophosphamide falling between the two and not being significantly different from either (P = 0.0005). The CHIP containing arm caused more thrombocytopenia than the other arms which were of equal toxicity (P less than 0.0005). Serum creatinine showed a gradual significant overall rise with each course of cisplatin/cyclophosphamide therapy (P less than 0.0005), whereas the CBDCA arm showed no change and the CHIP arm showed a small fall in serum creatinine after most courses of therapy. This study showed that CHIP or CBDCA in combination with cyclophosphamide was less toxic than cisplatin/cyclophosphamide therapy with regard to alopecia, degree and duration of nausea and vomiting, renal toxicity, neurotoxicity and anaemia. The CHIP/cyclophosphamide regimen caused more thrombocytopenia and diarrhoea. The CHIP and CBDCA containing arms caused more leukopenia than the cisplatin containing regimen. Either iproplatin or carboplatin would be an acceptable alternative to cisplatin in chemotherapy regimens, and would result in reduced toxicity.

Aged↗

PubMedDate not supplied

Growth inhibition of a prostate tumor by alpha-difluoromethylornithine and by cyclophosphamide.

The effects of the ornithine decarboxylase suicide substrate, difluoromethylornithine (DFMO), and of cyclophosphamide, individually and in combination, on the growth of the R3327MAT-Lu prostate derived tumor were determined. DFMO decreased the growth rate and resulted in a 75% reduction in DNA content compared to the control group. Cyclophosphamide produced a greater inhibition of growth and resulted in a 96% reduction in DNA content relative to the control. DFMO in combination with cyclophosphamide provided no greater inhibition of tumor growth than that of cyclophosphamide as a single agent. Further, in the schedule used in this experimental protocol the toxicity to the host of the drug combination was additive.

Animals↗

PubMed1983

Growth pattern of tumor xenografts in Wistar rats after treatment with cyclophosphamide, total lymphoid irradiation and/or cyclosporin A.

Wistar rats treated with cyclophosphamide, total lymphoid irradiation (TLI), and/or cyclosporin A (CSA) develop a state of immune suppression permitting the growth of tumor xenografts. Experiments were carried out on this newly developed model to investigate the growth patterns of a mouse osteosarcoma and a human colon adenocarcinoma. The combination of cyclophosphamide and CSA permitted a limited period of growth of the mouse osteosarcoma with a tumor take rate of 66%. No takes were observed with the human adenocarcinoma. The combination of cyclophosphamide and TLI resulted in a period of immunosuppression followed by recovery of the immune status. During the period of immunosuppression, tumor xenografts showed a 100% take rate. The most efficient immunosuppression was achieved by a combination of cyclophosphamide, TLI and CSA administered on alternate days. Wistar rats subjected to this treatment showed prolonged tolerance to mouse osteosarcoma and human adenocarcinoma xenografts. There was no alteration in the tumor doubling time or histological morphology of the xenografts in the adapted host as compared with those in the donor tumors. The tumor growth curve showed a pattern of initial growth, a period of stagnation, followed by a steady but slower growth phase. The significance of the results and the advantages of the rat model described in this paper for human tumor xenotransplantation are discussed.

Adenocarcinoma↗

PubMed1988

In vitro/in vivo effects of Mesna on the genotoxicity and toxicity of cyclophosphamide--a study aimed at clarifying the mechanism of Mesna's anticarcinogenic activity.

Cyclophosphamide is an effective antitumor agent with considerable side effects such as urotoxicity and carcinogenicity. These negative attributes may be caused by toxic and genotoxic metabolites, respectively. Mesna (sodium 2-mercaptoethane sulfonate) decreases the urotoxicity by scavenging the toxic metabolite acrolein. The present study was aimed at elucidating whether a similar scavenging of genotoxic alkylating intermediates could be found, which might cause the reduction in carcinogenicity. In vitro studies on the genotoxic and toxic properties of cyclophosphamide and its major metabolites to bacteria were therefore performed in the presence of Mesna. Mesna did not reduce the mutagenicity of any of the tested metabolites. Mesna clearly inhibited the toxic properties of acrolein. After in vivo application of Mesna and cyclophosphamide to rats, however, a lower yield of mutagens in the excreted urine was observed than after application of cyclophosphamide only.

Acrolein↗

PubMed1991

Uric acid as an inhibitor of biochemical changes induced by cyclophosphamide in mice.

The biochemical changes induced by uric acid, cyclophosphamide and uric acid plus cyclophosphamide were evaluated in Swiss albino male mice. Uric acid dissolved in water was administered orally in different doses for 7 days. Some mice from each group were injected intraperitoneally with cyclophosphamide (25 mg/kg) and sacrificed after 30 h. The blood of all animals was analyzed for uric acid levels. Uric acid was found not to affect the biosynthesis of nucleic acids and proteins in liver, testes and brain at 10-100 mg/kg/d. Pretreatment with uric acid provided significant protection against cyclophosphamide-induced impairment of DNA, RNA and protein biosynthesis.

Animals↗

PubMed1992

The effect of cyclophosphamide administration on the kidney of the rat.

In studies primarily designed to evaluate the effectiveness of chitosan as a treatment for cyclophosphamide-induced hemorrhagic cystitis in the rat, renal papillary necrosis and pyelonephritis were observed. Cyclophosphamide alone produced relatively mild renal changes. The combination of cyclophosphamide and intravesical instillation of acetic acid induced renal papillary necrosis (38 to 83% incidence) along with pyelonephritis, hydroureter and hydronephrosis. Chitosan, instilled in place of acetic acid, partially inhibited the induction of renal papillary necrosis. It appears that the presence of vesico-ureteral reflux with or without associated hydroureter and hydronephrosis is a prerequisite for cyclophosphamide-induced renal damage.

Acetates↗

PubMed1988

Combined thin-layer chromatography-photography-densitometry for the quantitation of cyclophosphamide and its four principal urinary metabolites.

A novel method for the quantitative determination of the anti-cancer drug cyclophosphamide and its principal urinary metabolites 4-oxocyclophosphamide, carboxyphosphamide, phosphoramide mustard and bis(2-chloroethyl)amine has been devised. The assay combines adsorption of drug-related material onto Amberlite XAD-2 and thin-layer chromatography with spot visualization using 4-(4-nitrobenzyl)pyridine, rapid photography and densitometry. The intra-assay coefficient of variation for each compound was less than 6%. The limit of detection of the assay was 1 microgram ml-1 for cyclophosphamide, phosphoramide mustard and bis(2-chloroethyl)amine and 0.5 microgram ml-1 for 4-oxocyclophosphamide and carboxyphosphamide. The method was validated for cyclophosphamide and 4-oxocyclophosphamide using gas chromatography. It is concluded that the method provides the first means of determining the full metabolic spectrum for cyclophosphamide in patients without recourse to the administration of radioisotopically labelled drug.

Biotransformation↗

PubMed1993

Determination of cyclophosphamide in urine by gas chromatography-mass spectrometry.

A sensitive gas chromatographic method for the determination of cyclophosphamide in urine is presented. After liquid-liquid extraction with diethyl ether and derivatization with trifluoroacetic anhydride, cyclophosphamide was identified and quantified with mass spectrometry. The method is suitable for the determination of cyclophosphamide at concentrations of more than 0.25 ng/ml, which enables the uptake of cyclophosphamide during occupational activities, such as the preparation and administration of antineoplastic agents in hospitals, to be measured. Simple preparation makes the method appropriate for routine analysis.

Cyclophosphamide↗

PubMed1990

Cyclophosphamide and prednisolone exacerbate the severity of intestinal paratuberculosis in Mycobacterium paratuberculosis monoassociated mice.

In this study we examined the effects of continuous oral administration of the immunosuppressive agents cyclophosphamide and prednisolone on the susceptibility of gnotobiotic nu/+ BALB/c mice to intestinal paratuberculosis. Treatment with either cyclophosphamide or prednisolone led to fecal shedding of Mycobacterium paratuberculosis, and increased the numbers of M. paratuberculosis recovered from the intestinal tract and liver, to levels similar to those recovered from untreated nu/nu mice. Numerous acid-fast bacilli and granulomas were observed within the intestinal tracts and livers of cyclophosphamide and prednisolone treated nu/+ and untreated nu/nu mice. In contrast, untreated control nu/+ mice infrequently shed small numbers of bacilli, harbored low numbers of M. paratuberculosis in their intestinal tracts, and did not have visible granulomas and acid fast bacilli in their tissues. Spleen cells from cyclophosphamide and prednisolone treated nu/+ mice, and from untreated nu/nu mice, had a reduced ability to proliferate in vitro in response to mitogen and antigens. These observations are consistent with previous evidence that cellular immunity restricts the development of intestinal paratuberculosis.

Animals↗

PubMed1988

Effect of "activated" cyclophosphamide on mouse oocyte in vitro fertilization and cleavage.

To investigate the involvement of oocytes in the mechanism of chemotherapy-induced ovarian failure, ovulation was induced in mice using pregnant mares' serum gonadotropin and human chorionic gonadotropin. Oocytes (with cumulus) were incubated for 4 hours with "activated" cyclophosphamide, 4-hydroperoxycyclophosphamide (PCTX) at 0, 1, 10, 100, and 500 micrograms/mL. Oocytes were then washed, fertilized with sperm obtained from nontreated male proven breeders, and incubated for 4 days. "Activated" cyclophosphamide inhibited dissolution of the cumulus and reduced fertilization and early cleavage rates in a dose-related manner. The data demonstrate that exposure of oocytes to cyclophosphamide metabolites in vitro adversely affects oocyte function. Oocytes may be involved in the mechanism of cyclophosphamide-induced ovarian failure.

Animals↗

PubMed2005

Altered muscarinic receptor subtype expression and functional responses in cyclophosphamide induced cystitis in rats.

In the in vitro study, it was investigated whether the expression of muscarinic receptors and cholinergic responses were altered in the situation of experimental cystitis. Rats were treated with cyclophosphamide intraperitoneally and the bladders were excised 36-100 h later. Immunohistochemistry and immunoblotting showed all subtypes of the muscarinic receptor (M1-M5) to be present in the specimens from inflamed urinary bladders and controls. In the cyclophosphamide-treated rats, the expression of muscarinic M5 receptors was increased by more than 40 times (p<0.01; n=8) both in the smooth muscle and the urothelium. Both the maximal contractile response to carbachol and to a high potassium concentration was approximately halved in cyclophosphamide-treated tissues, whereas the reduction was substantially greater in response to low carbachol concentrations (<EC(50)). The administration of 4-DAMP inhibited the carbachol-induced contractile responses of inflamed strips less potently than of controls, whereas pirenzepine and methoctramine showed equipotency in the two groups. The nitric oxide synthase inhibitor l-NNA increased the contractile effect of carbachol in inflamed detrusor strips, while it had no effect in controls. Immunoblotting showed endothelial nitric oxide synthase (eNOS) to be up-regulated in cystitis, and immunohistochemistry revealed the change to occur in the urothelium and in the suburothelial layer. The alteration of cholinergic detrusor responses in cyclophosphamide-treated rats depends mainly on a general detriment of contractility but also on indirect effects possibly via nitric oxide synthesis. The most prominent histological alterations occurred in the urothelium in which muscarinic M5 receptors increased in particular. The study further underlines that the urothelium may play significant roles in the pathogenesis of urinary bladder disorders such as interstitial cystitis.

Animals↗

PubMed2004

Regulation of activity of cathepsins B, L, and D in murine lymphosarcoma model at a combined treatment with cyclophosphamide and yeast polysaccharide.

Changes in the activity of cysteine (cathepsins B and L) and aspartyl (cathepsin D) proteases were investigated at the development of susceptible and resistant variants of murine lymphosarcoma (LS). It has been demonstrated that the variant resistant to the cyclophosphamide treatment is characterized by a lower activity of all three cathepsins in the tumor tissue. Application of a higher dose of cyclophosphamide led to a more pronounced increase of the studied enzymatic activity in mice with a resistant variant of LS, than in those with a susceptible one. Administration of a yeast polysaccharide derivative - sulfoethyl glucan - enhanced therapeutic effect of cyclophosphamide in mice with both variants of LS, while the most efficient dose was found to be that of 10mg/kg body mass. In the intact mice, usage of both cyclophosphamide and sulfoethyl glucan led to a similar increase of the cathepsins activity in liver and spleen.

Animals↗

PubMed2006

Potentiation of cyclophosphamide chemotherapy using the anti-angiogenic drug thalidomide: importance of optimal scheduling to exploit the 'normalization' window of the tumor vasculature.

The aim of this work was to study how administration schedule affects potentiation of cyclophosphamide, an alkylating agent, by thalidomide, an anti-angiogenic agent. Tumor oxygenation after thalidomide administration was determined over time by EPR oximetry. Such measurements provide a surrogate marker for determining the timing of 'normalization' of tumor vasculature. Re-growth delays were measured using different combinations and schedules of treatments. Additionally, the uptake of the metabolite of cyclophosphamide (hydroxycyclophosphamide or OH-CP) into tumors was determined by high performance liquid chromatography/tandem mass spectrometry (HPLC/MS/MS). A significant increase in pO(2) was observed after 2 and 3 days of treatment before eventually declining on day 4. Thalidomide potentiated the effect of cyclophosphamide only when cyclophosphamide was administered after 2 days of treatment with thalidomide (no significant benefit using other schedules). In this time frame, the HPLC/MS/MS measurements showed that the quantity of OH-CP penetrating into the tumor was about twice in mice treated by thalidomide compared to controls. In conclusion, the present study demonstrates that the benefit of combined therapy using an anti-angiogenic agent with a cytotoxic agent requires knowledge of the time window during which the vessels initially become normalized.

Angiogenesis Inhibitors↗

PubMed2005

Effect of squalene on cyclophosphamide-induced toxicity.

BACKGROUND: Toxicity due to drugs used for neoplastic disorders is extensively documented. Cyclophosphamide (CYP) is a widely used antineoplastic drug, which could cause toxicity of normal cells due to its toxic metabolites. We evaluated the protective role of squalene (SQ) in the toxicity induced by cyclophosphamide. METHODS: The activities of serum marker enzymes, clinical chemistry parameters and histopathology studies were done according to the standard procedures in the control and experimental groups of rats. RESULTS: Toxicity of the organs like heart, kidney and liver was evidenced from significant (P<0.05) increases of CK, LDH, AST, ALT, ALP, urea, creatinine and total bilirubin in cyclophosphamide- (150 mg/kg for 2 days) administered rats. Abnormal activities of these enzymes in the organs and serum total protein and cholesterol were also observed. No significant changes were observed in triglycerides in serum. Squalene oral treatment exerted protection towards these organs at a dose of 0.4 ml/day/rat. Histopathological examinations also confirmed the protective efficacy of squalene. CONCLUSION: Squalene may be efficacious as a cytoprotectant in cyclophosphamide-induced toxicities.

Administration, Oral↗

PubMed2005

Protective effect of bioactive fraction of Sphaeranthus indicus Linn. against cyclophosphamide induced suppression of humoral immunity in mice.

The bioactive fraction of Sphaeranthus indicus produced dose dependent increase in humoral immunity and delayed type hypersensitivity (DTH) response as evidenced by increased antibody production and increase in paw edema. The activity at higher doses, however, declines. Humoral antibody (HA) titre lowered by cyclophosphamide (CP) (p < 0.05) was enhanced by bioactive fraction at doses of 200 (p < 0.05) and 400 mg/kg (p < 0.001). There was dose dependent increase in HA titre in normal as well as immunosuppressed animals indicating that drug is effective in humoral immunity. Animals treated with cyclophosphamide and receiving bioactive fraction showed significant change in DTH response, which directly correlates with cell-mediated immunity, as compared to cyclophosphamide alone. Thus, it can be observed that a bioactive fraction of Sphaeranthus indicus acts as potentiator of DTH. Furthermore, the HPTLC fingerprint profile of the bioactive fraction was established to facilitate its identification and characterization. The results suggest that bioactive fraction influences both humoral and cell-mediated immunity and offers protection against immunosuppression induced by the cytotoxic agent cyclophosphamide.

Animals↗