Antineoplastic Drugs Cyclophosphamide Research Articles

Inhalation and dermal exposure to eight antineoplastic drugs in an industrial laundry facility

The aims of the study were to quantify levels of dermal and inhalation exposure to antineoplastic drugs in an industrial laundry service in the Netherlands and to test the removal efficiency of the washing procedure for removal of antineoplastic drugs. During four workdays dermal and inhalation exposure to eight frequently used antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, 5-fluorouracil, etoposide, cytarabine, gemcitabine and chlorambucil) were measured for all job titles involved in handling unwashed laundry. To test the removal efficiency of the washing procedure, 10 x 10 cm sections were excised before and after the washing procedure. These sections were taken from 15 bed sheets that were collected in hospitals of patients who were treated with one of the selected antineoplastic drugs. During none of the four measurement days, detectable levels of any of the eight antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, 5-fluorouracil, etoposide, cytarabine, gemcitabine, or chlorambucil) were found on workers' skin of hands or in any of the air samples. Only four out of the 15 bed sheets from patients that were treated with antineoplastic drugs appeared to be contaminated with detectable levels of antineoplastic drugs before the washing procedure (range 13.0-3,060 ng/100 cm(2)). After the pre-washing and after the complete washing procedure, no detectable levels of any of the eight antineoplastic drugs were found anymore in the selected bed sheets. The implementation of guidelines for working with antineoplastic drugs seems to be successful in reducing exposure to antineoplastic drugs of workers in this laundry facility to an acceptable, non-detectable level and to remove antineoplastic drug contamination from bed linen.

Dl-α-lipoic acid ameliorates cyclophosphamide induced cardiac mitochondrial injury

Mitochondria play a central role in heart metabolism and function. Administration of antineoplastic drug cyclophosphamide (CP) adversely affects the heart mitochondria which may result in cardiotoxicity. The present study is aimed at evaluating the role of lipoic acid (LA) in CP induced myocardial injury. Male albino rats of Wistar strain were used for the study. CP was administered as a single intraperitoneal injection (200 mg/kg BW). A decrease in the activities of TCA cycle enzymes such as succinate dehydrogenase, malate dehydrogenase and isocitrate dehydrogenase was noted in CP treated rats. Simultaneously there was a decrease in the activities of mitochondrial complexes of electron transport chain. Decrease in the activities of these enzymes suggests a loss in mitochondrial function and integrity. Ultrastuctural observations were also in agreement with the above abnormal changes. Loss of myofilaments and damage of mitochondrial cristae revealed the cytotoxic effect of CP. The supplementation of LA (25 mg/kg BW) restored the above abnormalities to near normalcy. The study brings out the importance of LA in improving the mitochondrial function in cardiac cells after CP administration.

Cytotoxicity of some Russian ethnomedicinal plants and plant compounds

The cytotoxic action of crude ethanol extracts from 61 plant species used in Russian ethnomedicine for alleviating symptoms of diseases in cancer patients was studied on cultured human lymphoblastoid Raji cells. Extracts from Chelidonium majus, Potentilla erecta, Chamaenerium angustfolium, Filipendula ulmaria and Inula helenium possessed marked cytotoxicity, suppressing the growth of the cells at concentrations of 10 and 50 microg/mL. The cytotoxicity of purified active compounds from selected plant species was evaluated along with pharmaceutical antineoplastic drugs methotrexate, fluorouracil, cyclophosphamide and vinblastine. Sesquiterpene lactones helenin, telekin and artemisinin, aromatic polyacetylene capillin, and alkaloid preparation sanguirythrine suppressed cell growth at concentrations of 1-2 microg/mL, which exceeds the cytotoxicity of cyclophosphamide and fluorouracil.

Pathogenesis of pneumococcal pneumonia in cyclophosphamide-induced leukopenia in mice.

Streptococcus pneumoniae pneumonia frequently occurs in leukopenic hosts, and most patients subsequently develop lung injury and septicemia. However, few correlations have been made so far between microbial growth, inflammation, and histopathology of pneumonia in specific leukopenic states. In the present study, the pathogenesis of pneumococcal pneumonia was investigated in mice rendered leukopenic by the immunosuppressor antineoplastic drug cyclophosphamide. Compared to the immunocompetent state, cyclophosphamide-induced leukopenia did not hamper interleukin-1 (IL-1), IL-6, macrophage inflammatory protein-1 (MIP-1), MIP-2, and monocyte chemotactic protein-1 secretion in infected lungs. Leukopenia did not facilitate bacterial dissemination into the bloodstream despite enhanced bacterial proliferation into lung tissues. Pulmonary capillary permeability and edema as well as lung injury were enhanced in leukopenic mice despite the absence of neutrophilic and monocytic infiltration into their lungs, suggesting an important role for bacterial virulence factors and making obvious the fact that neutrophils are ultimately not required for lung injury in this model. Scanning and transmission electron microscopy revealed extensive disruption of alveolar epithelium and a defect in surfactant production, which were associated with alveolar collapse, hemorrhage, and fibrin deposits in alveoli. These results contrast with those observed in immunocompetent animals and indicate that leukopenic hosts suffering from pneumococcal pneumonia are at a higher risk of developing diffuse alveolar damage.

Effect of thymus-dependent antigen on recovery of hemo- and lymphopoiesis impaired by antineoplastic drugs.

Single injection of antineoplastic drugs cyclophosphamide and cisplatin (Platidiam) in maximum permissible doses to CBA/CaLac mice impaired morphological composition of hemopoietic and lymphoid organs (thymus and spleen). Drug-induced changes persisted for 6 months. Cyclophosphamide caused more severe disturbances in the lymphoid stem in the bone marrow, thymus, and spleen and more strongly stimulated erythropoiesis in the spleen compared to cisplatin. Immunization of mice with thymus-dependent antigen (sheep erythrocytes) after injection of cytostatics accelerated regenerative processes in hemopoietic and lymphoid organs. However, cell disorganization 3 and 6 months after immunization did not differ from that caused by antineoplastic drugs and was even more pronounced in the thymus by the 6th month of observations.

Pharmaceuticals in the environment--a human risk?

Pharmaceuticals in the environment and their potential toxic effects are emerging research areas, which is also reflected in the drug approval regulation. This far, focus has mainly been directed toward potential effects on nature and wildlife. In this paper, human risk as a consequence of exposure via the environment has been addressed and assessed. The synthetic estrogen 17alpha-ethinylestradiol (EE2), the antibiotic phenoxymethylpenicillin (Pen V), and the antineoplastic drug cyclophosphamide (CP) were chosen as modeling substances based on criteria of receptor specificity, elevated risk for human population groups for which the pharmaceuticals are not therapeutically intended, different modes of action, and prescription frequency. Attention has been focused on emissions from the use phase and subsequent diffuse release via the sewer systems. A reasonable worst-case environmental fate and human exposure were estimated using the software EUSES on worst-case emission quantities. The results indicate a negligible human risk connected to the environmental exposure for these substances. Danish conditions have been used as the modeling area, but the results are assumed to be valid for regions with similar drug consumption profiles.

In Vivo Effects of Millimeter Waves on Cellular Immunity of Cyclophosphamide-Treated Mice

Reactions of peritoneal macrophages (PM) and T lymphocytes of BALB/c mice to in vivo exposure to millimeter (MM) waves were studied. The mice were additionally treated with the antineoplastic drug cyclophosphamide (CPA) 100 mg/kg. Phagocytosis of Candida albicans cells by PM obtained from mice treated with CPA and MM waves, alone and in combination, was studied in vitro using a monolayer technique. Proliferation of murine T cells (splenocytes) was studied by 3H-thymidine incorporation into DNA of T lymphocytes without stimulation and after stimulation with anti-CD3 antibody 2C11. The results of this study show that 61.22 GHz MM waves with an incident power density of 15 mW/cm2 and a peak SAR of 420 W/kg significantly reduce the toxic effects of CPA on cellular immunity of mice in vivo as observed by the increased PM phagocytic activity and enhancement of T-cell proliferation.

Thermodynamic investigation of camel retina acetylcholinesterase inhibition by cyclophosphamide.

The present work addresses the estimation of energy parameters such as Gibb's free energy change (delta G), enthalpy change (delta H); entropy change (delta S) and activation energy (E a) of acetylcholinesterase (AChE, EC 3.1.1.7) from camel retina in the absence and presence of the antineoplastic drug cyclophosphamide (CP). A spectrophotometric method was used for the determination of AChE activity, which was the basis for determination of these parameters. The PZ factor (number of sterically and energetically favorable collisions occurring between CP and AChE) have also been studied in this investigation. The energy parameters obtained in the present investigation were compared with the values reported elsewhere.

Modulation of cyclophosphamide mutagenicity by vitamin C in the in vivo rodent micronucleus assay.

The modulatory effect of vitamin C (Vit C) on the mutagenic effect of the antineoplastic drug cyclophosphamide (CP) was assessed in the in vivo micronucleus test in Swiss mice. Simultaneous oral administration of Vit C with i.p. administration of CP was found to decrease the frequency of micronucleated polychromatic erythrocytes elevated by CP. Vit C exhibited a significant antimutagenic effect over a wide dose range (1.56-200 mg/kg). The dose-response relationship was highly significant. These results demonstrated the ability of the in vivo micronucleus test to detect in vivo modulation of CP mutagenicity by Vit C. Our earlier results and those from other laboratories also indicate that this model system is suitable for primary in vivo screening of modulation of mutagenesis.

Combinations of Antifungal and Antineoplastic Drugs with Interactive Effects on Inhibition of Yeast Growth

Interactive effects among antifungal and antineoplastic drugs contributed to toxicities when combinations of these drugs were used to inhibit the growth of five Candida spp. Drug interactions were measured by growth inhibition in both liquid and solid media, by viable cell counts and by examination using scanning electron microscopy. Large cooperative effects on toxicity were demonstrated between some antineoplastic and antifungal drugs. For example, positive cooperativity was seen between the antineoplastic drug 5-fluorouracil and combinations of the antifungal agents amphotericin B and miconazole nitrate. Smaller, and often negative, interactions occurred between the antineoplastic drug cyclophosphamide and antifungal drugs. The levels of drugs required for inhibition in combination drug treatments were critically dependent upon the ratios as well as the absolute concentrations of the drugs tested. Drug combinations were selected which inhibit yeast growth at concentrations far below the individual MIC of the drugs. These combinations may prove of value in clinical treatments of cancer patients infected by Candida.

Cytogenetic interactions of contrast media and antineoplastic drugs.

The cytogenetic interactions of ionic (diatrizoate, ioxaglate) and nonionic (iohexol) contrast media (CM) with antineoplastic drugs cyclophosphamide (CPA) and carmustine (CARM) were evaluated in a rat bone marrow cell model. Male Wistar rats were anesthetized with a 6% chloral hydrate solution and divided into five groups of five rats each. In protocol 1, three groups of rats received diatrizoate, ioxaglate, and iohexol (2.5 mL/kg) intravenously within 30 seconds. The remaining two groups were similarly injected with CPA and CARM (10 mg/kg). Control animals were injected with nonpyrogenic sterile water or saline solution. After 12 and 24 hours, the animals were killed with an overdose of chloral hydrate, and bone marrow smears were prepared for determining chromosomal damage in polychromatic erythrocytes (PCEs) by a micronucleus test. In protocol 2, CPA and CARM were injected, and 15 minutes later, bolus injections of diatrizoate, ioxaglate and iohexol were given through the same route. Both ionic and nonionic CM induced significant numbers of micronuclei in PCEs (P less than .05). CPA caused a severe cytogenetic effect, whereas CARM did not produce a significant number of micronuclei in PCEs compared with control. In protocol 2 experiments, antagonism with CPA and synergism with CARM was demonstrable. Clinical implication of the cytogenetic interactions between CM and antineoplastic drugs remains to be established.

Organ-associated macrophage precursor activity: isolation of candidacidal and tumoricidal effectors from the spleens of cyclophosphamide-treated mice.

We recently reported the modulating effects of a single injection of the anti-neoplastic drug cyclophosphamide (Cy; 150 mg/kg i.p.) on in vivo resistance against the experimental Candida albicans infection. Increased resistance to microbial challenge occurred 12 to 18 days after treatment. We now show that the increased resistance is paralleled by the appearance of potent nonadherent nonphagocytic effectors in the spleen (day 12) that are capable both of candidacidal activity and natural killer (NK) activity against YAC-1 cells. The cells mediating the two reactivities have a low buoyant density, a strong proliferating activity in response to the macrophage colony stimulating factor (CSF-1), and are unable to kill the NK-insensitive lines EL-4 and P815. A clear cut isolation of macrophage precursor cells from this Percoll low density fraction has been performed in an indirect rosette assay on the basis of their positivity for the surface markers recognized by the highly specific rat-anti-mouse macrophages, monoclonal antibodies M143 and F4/80. We obtained an extremely homogeneous population of cells in the early stage of macrophage differentiation that is responsible for all the candidacidal activity and for a major part of the NK activity observed in the spleen of Cy-treated mice, and which is extremely sensitive to CSF-1 induction.

Determination of the underivatized antineoplastic drugs cyclophosphamide and 5-fluorouracil and some their metabolites by capillary gas chromatography combined with electron-capture and nitrogen phosphorus selective detection

A rapid and sensitive method for the determination of cyclophosphamide (CP) and 5-fluorouracil (5-FU) and some of their metabolises in one analysis has been developed. Surface-coated open-tubular OV-275 columns were combined with electron-capture detection and nitrogen phosphorus selective detection. The influence of the column diameter on the separation is shown. Extraction with 2-propanol-diethyl ether (22:77) allows the isolation of CP, 5-FU and their analogues in one extraction step. The assay was applied to some pharmacokinetic experiments with chemotherapeutically treated patients and with a WAG/Rij rat.

Initial effects of cyclophosphamide on urinary bladder epithelium in the rat

<h2>Summary</h2> The antineoplastic drug cyclophosphamide may cause urinary bladder damage in the form of a sterile haemorrhagic cystitis. This has been found to be due to concentration of cyclophosphamide metabolites in the bladder. A light and ultrastructural study was made of the effects of the drug on the urinary bladders of rats, comparing the effects of small doses administered over two weeks with those of a comparable total dose administered in one injection. Initially minor cytoplasmic changes were seen, and later stripping of the thick luminal membrane. Multivesicular debris, vacuolation and collapse of fusiform vesicles in superficial and intermediate cells was a further stage. Sloughing of whole layers of degenerating cells occurred after a single heavy dose.