Antitumor Activity Of Cyclophosphamide Research Articles

Assessment of the Antimetastatic Activity of Extracts of Filipedula ulmaria Depending on Extractant

Three extracts were produced from the above-ground part of the meadowsweet Filipendula ulmaria (L.) Maxim. using water, 40% ethanol, and 70% ethanol. Comparative assessment of their actions on the development of Lewis lung carcinoma (LLC) in C57Bl/6 mice showed that isolated administration led to inhibition of the development of the metastatic process by meadowsweet extracts prepared with water and 70% ethanol, with no effect on growth of the primary tumor. Comparative evaluation of the effects of meadowsweet extracts on the antitumor activity of cyclophosphamide (CP) in relation to primary tumors revealed no change in the efficacy of the cytostatic agent. Inclusion of meadowsweet extracts at doses of 25 and 50 mg/kg in the therapeutic regimen of mice with LLC produced significant increases in the antimetastatic action of CP using the aqueous extract (the indexes of inhibition of metastasis (IIM) were 75% and 98%). Meadowsweet extract prepared with 40% ethanol had no effect on the development of the tumor process in mice with LLC or the efficacy of CP treatment.

The MODULATORY EFFECTS OF BONE MARROW-DERIVED MESENCHMAL STEM CELLS ON CYCLOPHOSPHAMIDE INDUCED HEPATOTOXICITY IN CARCINOMA MICE

Objective: Cyclophosphamide (CPA) is a chemotherapeutic agent, induces hepatotoxicity as one of its side effects. Therefore, the present work was designed to investigate the protective role of bone marrow-derived mesenchymal stem cells (BM-MSCs) on CPA–induced hepatotoxicity in Ehrlich Ascites Carcinoma bearing-mice (EAC) and to test whether BM-MSCs influences the antitumor properties of the CPA.
 Methods: The hepatoprotective effects of BM-MSCs (single dose of 100 µl of a cell suspension containing allogenic BM-MSCs, i. v.) was evaluated in a model of hepatotoxicity by CPA (10 mg/kg/d i. p.) in EAC-female mice for one month. The anti-tumor activities of CPA and BM-MSCs were assessed by measuring mean tumor weight, mean survival time and the increase in life span. Moreover, ALT, AST, GGT, MDA, GSH, SOD, IL-6, IL10, caspase-3 and Bcl2 were measured.
 Results: The i. p. administration of CPA and BM-MSCs resulted in significant reductions in tumor size and mean tumor weight as well as caused concurrent significant increases in the life span as compared to the EAC mice. Furthermore, BM-MSCs ameliorated the liver enzyme markers namely ALT, AST, GGT, and hepatic oxidative stress through inhibition of MDA level that correlated with significant improvement in antioxidant status via increasing GSH and SOD levels as compared to both EAC and EAC+CPA groups. Moreover, BM-MSCs treatment significantly reduced the inflammatory marker level IL-6 as well as increment the level of IL-10 with subsequent decreases apoptosis via a depletion in the caspase-3 associated with an enhancement in the level of Bcl2 as compared to EAC group and EAC+CPA group. Minor histological lesions were observed in the liver tissue sections of mice treated with CPA and BM-MSCs as compared to the high histological lesions observed in the liver of the EAC group and CPA treated group.
 Conclusion: These results concluded that the combination treatment of BM-MSCs with CPA exhibited promising potential antitumor efficacy with greater safety than CPA treatment alone in mice via its antioxidant, anti-inflammatory and antiapoptotic effects.

Sorbus aucuparia L. Fruit Is a Source of the Drug for Increasing the Efficiency of Tumor Chemotherapy

The composition of phenolic compounds of rowanberry (Sorbus aucuparia L.) fruit extracts prepared with 40% ethanol and 95% acidified ethanol was studied. The differences in the content of flavonoids, including anthocyanins, and phenolic acids were shown. It was found that the antimetastatic activity of cyclophosphamide was most efficiently increased by the rowanberry fruit extract in 95% acidified ethanol enriched in anthocyanins. The aim of the present research was to investigate the effect of hydroalcoholic extracts of rowanberry fruit on the development of Lewis lung carcinoma and the antitumor activity of cyclophosphamide and to reveal the most effective extract containing a phenolic complex for its further study as a promising drug.

FRUITS OF SORBUS AUCUPARIA L. ARE SOURCE DRUG FOR INCREASE OF TUMORS EFFECTIVENESS CHEM-OTHERAPY

The composition of phenolic compounds of extracts of rowanberry (Sorbus aucuparia L.) fruit, prepared with 40% ethanol and 95% acidified ethanol was studied. Differences in the content of flavonoids, including anthocyanins, and phenolic acids have been established. It was found that the most efficiently increases the antimetastatic activity of cyclophosphamide extract of rowan fungi on 95% acidified ethanol enriched with anthocyanins. The purpose of the study was to: study the effect of hydroalcoholic extracts of rowan fungi on the development of Lewis lung carcinoma and the antitumor activity of cyclophosphamide; to reveal the most effective extract containing a phenolic complex, for further study as a promising drug.

Cyclophosphamide analogues: synthesis, spectroscopic study, and antitumor activity of diazaphosphorinanes

Some diazaphosphorinanes were synthesized and characterized by 1H, 13C, 31P NMR and IR spectroscopy and elemental analysis. The antitumor activity of cyclophosphamide (CP) and its nine analogoues with formula Open image in new window , R = OC6H5CH3-4 (1), NHC6H4S(O)2NH2-4 (2), NHC(O)NHC6H4-CH3-2 (3), NHC(O)NHC6H4-NO2-2 (4), NHC(O)NHC6H4-NO2-3 (5), NHC(O)NHC6H4-NO2-4 (6), NHC(O)C6H4-NO2-2 (7), NHC(O)C6H4-NO2-3 (8), and NHC(O)C6H4-NO2-4 (9) were evaluated by cell culture on K562 cell line using MTT cell proliferation assay. The IC50 values for CP and the compounds 1–9 were in the range of 0.140 (for 3) to 58.250 μM (for 2). It was found that compounds 3–6 are the best candidates for antitumor activity close to CP. Compound 2 containing aminosulfonamide substituent is very much less toxic among these compounds.

Cyclophosphamide and ascorbic acid-mediated ultrastructural and biochemical changes in Dalton's lymphoma cells in vivo

Cyclophosphamide, an antineoplastic drug effective against a wide variety of cancers is cytotoxic to normal cells also. Ascorbic acid (vitamin C) at higher concentrations possesses cytotoxic effects and it can also enhance the cytotoxicity of 5-fluorouracil in a dose-dependent manner in mouse lymphoma. In the present study, effect of cyclophosphamide treatment alone and in combination with ascorbic acid in vivo on the ultrastructure and some biochemical changes in Dalton's lymphoma tumor cells were investigated . Cyclophosphamide treatment causes disappearance of cell membrane processes, thickening and reduction in the number of mitochondrial cristae as well as the manifestation of rounded shape of mitochondria. The combination treatment with ascorbic acid plus cyclophosphamide caused further changes in tumor cells showing disintegration in the cell surface membrane, disruption in the nuclear membrane and roundish mitochondria with reduction and disruption in the mitochondrial cristae. The observed ascorbic acid plus cyclophosphamide-mediated decrease in reduced glutathione (GSH) in tumor cells may play an important role in the antitumor activity of cyclophosphamide by weakening cellular antioxidant-mediated defense mechanism, thereby increasing tumor cell's susceptibility to cell death. The cyclophosphamide-mediated decrease in lactate dehydrogenase activity in tumor cells and simultaneous increase in ascites supernatant may possibly indicate alteration in the membrane permeability of tumor cells for lactate dehydrogenase as well as tumor cell injury. Further investigation should determine detailed mechanism(s) involved in cyclophosphamide-induced ultrastructural and biochemical changes in tumor cells.

Oxymatrine promotes the antitumor activity of cyclophosphamide against Lewis lung carcinoma in mice

Objective:To observe the anti-tumor activity of oxymatrine alone or in combination with cyclophosphamide a- gainst Lewis lung carcinoma in mice and to discuss the related mechanisms.Methods:Lewis lung carcinoma cells were trans- planted subcutaneously to establish cancer transplantation model in mice.Animals were orally given oxymatrine(80,40 and 20 mg/kg)alone or in combination with cyclophosphamide(30 mg/kg,gastric lavage).The mean tumor inhibitory rate was calcu- lated and the growth curve of tumors was plotted.Radio immunoassay(RIA)was used to determine the serum concentration of epidermal growth factor(EGF).Comparison was made between the treatment groups and the control group.Results..The in- hibitory rates were not significantly different between the control group and the pure oxymatrine treatment group.When com- bined with cyclophosphamide,the inhibitory rates of oxymatrine were significantly increased(P0.01).When at 80,40 and 20 mg/kg,oxymatrine inhibited tumor growth by 66.62%,61.70% and 59.04%,respectively.Also,when combined with cy- clophosphamide,oxymatrine at 40 and 80 mg/kg significantly decreased EGF levels compared with those of model group and pure oxymatrine groups(P0.01).Conclusion:Oxymatrine can enhance the inhibitory effect of cyclophosphamide against Lewis lung carcinoma,and the mechanism may be related to the decrease of serum EGF level.

Micronucleus and antitumor activities of two newly synthesized pyrimidine derivatives

Micronuclear and antitumor activities of two newly synthesized iodides of pyrazolo[1,5a]pyrimidines were investigated using mice model. It has been shown that both compounds are slightly toxic and have no antitumor activity in mice with Ehrlich's ascites carcinoma. Only one of them has weak micronuclear activity. Both compounds increase substantially micronuclear as well as antitumor activities of cyclophosphamide.

Antitumor and antimetastatic activity of fucoidan, a sulfated polysaccharide isolated from the Okhotsk sea Fucus evanescens brown alga

Antitumor and antimetastatic activities of fucoidan, a sulfated polysaccharide isolated from Fucus evanescens (brown alga in Okhotsk sea), was studied in C57Bl/6 mice with transplanted Lewis lung adenocarcinoma. Fucoidan after single and repeated administration in a dose of 10 mg/kg produced moderate antitumor and antimetastatic effects and potentiated the antimetastatic, but not antitumor activities of cyclophosphamide. Fucoidan in a dose of 25 mg/kg potentiated the toxic effect of cyclophosphamide.

Low-energy red light radiation improves antitumor activity of cyclophosphamide

Exposure of rats with Pliss lymphosarcoma to incoherent red light according to certain protocols creates conditions preventing suppression of antitumor resistance, reducing the toxic effect of cyclophosphamide, and potentiating its antitumor effect.

Effects of T-activin and vitamin E on toxicity and antitumor activity of cyclophosphamide.

We studied the effect of combination treatment with T-activin and vitamin E on acute toxicity and antitumor activity of cyclophosphamide in mice. Combined administration of these preparations 1.37-fold increased the maximum permissible dose of cyclophosphamide without affecting its LD(50)and delayed mouse death from cyclophosphamide toxicity. Most mice died only 3 days after combination treatment with the test preparations and cyclophosphamide in doses of LD(16)-LD(84). The second peak of death from hematologic toxicity of cyclophosphamide was absent under these conditions. T-activin and vitamin E did not abolish the antitumor effect of cyclophosphamide on mice with subcutaneously implanted P-388 lympholeukemia. Tumor growth was suppressed by 100%.

ChemInform Abstract: An Overview of Cyclophosphamide Development and Clinical Applications

In this overview of the pharmacology of the anticancer drug cyclophosphamide, a brief history of the development of this drug from the general class of nitrogen mustards is provided. The antitumor activity of cyclophosphamide and its isomer ifosfamide is discussed through considerations of metabolism, resistance, detoxification, and DNA cross-linking. Clinical uses in general chemotherapy, bone marrow transplantation and immunosuppression are presented. A review with 73 references.

P-263 - Antitumor activity of cyclophosphamide in model mouse bearing immunological liver injury

P-263 - Antitumor activity of cyclophosphamide in model mouse bearing immunological liver injury

The influence of Fluosol-DA and carbogen breathing on the antitumor effects of cyclophosphamide in vivo

The effects of Fluosol-DA, an oxygen-carrying perfluorochemical emulsion, and carbogen breathing alone or in combination on the antitumor activity of cyclophosphamide (CTX) in vivo were investigated. The addition of 12 ml/kg Fluosol-DA immediately prior to CTX treatment exerted no effect on the antitumor effect of CTX on the RIF-1 tumor in C3H mice. On the other hand, carbogen breathing alone for 8 h significantly enhanced the antitumor effect of CTX, with a dose-modification factor of 1.29 +/- 0.07. The combination of Fluosol-DA and carbogen breathing further increased the effect of CTX, with a dose-modification factor of 1.63 +/- 0.05. There was no significant difference in animal lethality within the treatment groups. It was concluded that Fluosol-DA in combination with carbogen breathing may be useful for the enhancement of CTX chemotherapy of human neoplasms.

Antitumor activity of cyclophosphamide and lipopolysaccharide in tumor-bearing mice pretreated with BCG.

Antitumor effects of cyclophosphamide (CY) and lipopolysaccharide (LPS) were investigated in BCG-treated mice. C3H/He mice and CDF1 mice were injected with BCG and were inoculated subcutaneously with syngeneic mouse hepatoma and mastocytoma P815 respectively. A subsequent injection of LPS caused hemorrhagic necrosis and retarded growth of tumor. When mice were treated with LPS plus suboptimal dose of CY, tumor growth was retarded and survival time was prolonged. The antitumor effects were more remarkable when mice were treated with CY prior to the injection of LPS. Without BCG pretreatment, LPS showed no antitumor activity in mice. Sera from mice treated with BCG plus LPS was cytotoxic for cultured tumor cells. However treatment of mice with CY did not increase the in vitro cytotoxicity. In this experimental condition, CY had no effect on delayed type hypersensitivity when evaluated by the footpad reaction to purified protein derivative (PPD). These results seem to indicate that the antitumor effects of the treatment with CY and LPS in BCG-treated mice are mediated by the reduction of tumor burden by CY and a serum factor induced by LPS.

Increased toxicity of the antitumor drug cyclophosphamide in mice in the presence of the volatile anesthetic agent halothane.

Exposure of mice to 0.5% halothane in air, which is close to a maintenance concentration in man, after an IP dose of cyclophosphamide produced an increase in the lethality of cyclophosphamide. The LD50 (30 day) for cyclophosphamide without halothane was 251 mg/kg; with 2 h subsequent exposure to halothane it was 152 mg/kg; and with 20 h subsequent exposure to halothane it was 158 mg/kg. The median survival time of mice receiving cyclophosphamide at doses between 137 and 240 mg/kg was more than 30 days in the absence of halothane, 12 days with 2 h halothane, and 10.5 days with 20 h halothane exposure. Survival of mice was decreased irrespective of whether 2 h halothane exposure preceded or followed cyclophosphamide administration. Separation of cyclophosphamide administration and preexposure to halothane by breathing air for 1 h abolished the decrease in survival. Halothane exposure for 2 h after cyclophosphamide had no effect on the antitumor activity of cyclophosphamide. Total-body clearance of cyclophosphamide in mice exposed to halothane was 60 ml/min/kg, as against 188 ml/min/kg in nonexposed mice. No change was produced by halothane in the area under the plasma concentration-time curve over 2 h for 4-hydroxycyclophosphamide following cyclophosphamide administration. The reason for the increased lethality of cyclophosphamide in the presence of halothane could not be determined. There was no increase in leukopenia caused by cyclophosphamide and no increase in bladder toxicity, in liver toxicity, in renal toxicity, or in the penetration of cyclophosphamide into the brain. The study, together with reports of increased toxicity in patients receiving cancer chemotherapy in close proximity to general anesthesia, should alert physicians and others to the possibility of an interaction between volatile anesthetic agents and chemotherapeutic drugs.

Carbon tetrachloride-induced increase in the antitumor activity of cyclophosphamide in mice: a pharmacokinetic study.

Carbon tetrachloride is an hepatotoxin that depresses hepatic microsomal cytochrome P-450 and other enzyme activities. Cyclophosphamide is an anticancer drug that is activated by hepatic microsomal cytochrome P-450, while the products of cyclophosphamide metabolism by cytochrome P-450 can be metabolized by other hepatic enzymes. Carbon tetrachloride pretreatment has been found to increase the in vivo antitumor activity of cyclophosphamide against murine leukemia P-388. Carbon tetrachloride did not, however, affect the direct cytotoxicity of cyclophosphamide or 4-hydroxycyclophosphamide to cells in culture. Pharmacokinetic studies in mice revealed a delayed plasma disappearance of cyclophosphamide after carbon-tetrachloride pretreatment with an apparent initial half-time of 20.4 min compared to 9.0 min in non carbon-tetrachloride-pretreated mice. Plasma levels of total alkylating activity and plasma 4-hydroxycyclophosphamide increased more slowly and reached a lower peak, but were maintained for a longer time period in mice pretreated with carbon-tetrachloride than in untreated mice. The half-life for plasma elimination of 4-hydroxycyclophosphamide in untreated mice was 12 min and in carbon-tetrachloride-pretreated mice 27 min. There was, however, no difference in the area under the curve for either plasma total alkylating activity or plasma 4-hydroxycyclophosphamide between the two groups. It is suggested that prolonged exposure of tumor cells to 4-hydroxycyclophosphamide might be responsible for the increased antitumor activity of cyclophosphamide following carbon-tetrachloride pretreatment.

Effects of chlordiazepoxide, diazepam and oxazepam on the antitumor activity, the lethality and the blood level of active metabolites of cyclophosphamide and cyclophosphamide oxidase activity in mice.

Effects of chlordiazepoxide, diazepam and oxazepam on the antitumor activity and acute toxicity of cyclophosphamide and the level of its active metabolites in the plasma were investigated in mice. Cyclophosphamide was administered 24 h after the final injection of chlordiazepoxide, diazepam or oxazepam (100 mg/kg/d for 3 d, i.p.). Pretreatment with these drugs increased the acute toxicity of cyclophosphamide (300 or 450 mg/kg, i.p.), whereas drugs had no effect on the antitumor activity of cyclophosphamide (100 mg/kg, i.p.) against Ehrlich solid carcinoma. A high level of active metabolites of cyclophosphamide in the plasma after the administration of cyclophosphamide (300 or 450 mg/kg, i.p.) was observed in chlordiazepoxide-, diazepam- or oxazepam-treated mice. On the other hand, chlordiazepoxide, diazepam or oxazepam enhanced significantly the activity of cyclophosphamide oxidase in hepatic microsomes. It is concluded that potentiation of the acute toxicity at a high dose of cyclophosphamide by chlordiazepoxide, diazepam and oxazepam is due to an induction of microsomal drug-metabolizing enzyme which are responsible for the in vivo activation of cyclophosphamide.

Cyclophosphamide and dimethylsulfoxide in the treatment of squamous carcinoma of the lung. Therapeutic efficacy, toxicity, and pharmacokinetics.

To determine whether dimethylsulfoxide (DMSO) can potentiate antitumor activity of cyclophosphamide (CYC) in patients with squamous cell carcinoma of the lung, 14 patients were treated with 5 l of a 5% or 6% DMSO solution PO over 3 days and 1,500 mg CYC/m2 IV as a 60-min infusion on the third day of treatment. Serial blood, CSF, and urine samples were collected to assess the pharmacokinetics of CYC. Courses were repeated every 3-4 weeks. No antitumor responses were observed. Toxicity was mainly hematologic and similar to that of CYC alone. There was one death from infection during granulocytopenia. Nonhematologic toxicity was moderate to severe and included nausea (14 patients) and vomiting (five patients). The plasma pharmacokinetics of CYC in this study are similar to previously reported results for CYC alone, but the 24-h urinary excretion of CYC in our study is much lower than previously reported. Further studies in tumors more responsive to CYC may be warranted.

制癌薬に関する薬物相互作用(第2報)免疫賦活薬投与マウスにおけるシクロホスファミドの抗腫瘍作用

The antitumor activities of cyclophosphamide (CPA) on Ehrlich solid tumor in mice were examined alone and in combination with immunopotentiators. Killed Mycobacterium butyricum (MB), OK-432 (Picibanil) and lipopolysaccharide (E. coli, LPS) prolonged the pentobarbital-induced sleeping time of mice with dose-dependence. MB and LPS markedly inhibited the antitumor activity of CPA. In MB-or LPS-treated mice, the analgesic action of aminopyrine was increased and the action of codeine phosphate was decreased. These immunopotentiators may change the activity of combined drugs by inhibition of the hepatic microsomal drug-metabolizing system.