Determination of ifosfamide by gas chromatography-mass spectrometry

Ifosfamide, an oxazaphosphorine, is thermally stable during elution in gas chromatography (GC) at temperatures above 200 °C, in contrast to its structural isomer cyclophosphamide. Both 2.65-µm and 0.32-µm OV-1 columns were efficient for GC of ifosfamide without derivatization. Mass spectrometry (MS), showed that intact ifosfamide was eluted without interference from naturally occurring metabolites in blood plasma. Ifosfamide can be monitored, by capillary GC—MS without derivatization, in blood plasma from cancer patients treated with the drug. Only a liquid-liquid extraction is required before injection of the sample. A single peak of ifosfamide is detected with molecular mass 260; fragmentation starts with loss of CH2Cl ([M — CH2Cl], m/z 211). The limit of determination for ifosfamide in human plasma was about 50 nM (10 ng ml-1). Recovery, quality of calibration curves and reproducibility were suitable for the rapid determination of ifosfamide in the range 0.01–1000 µg ml-1

In vitro and in vivo chemosensitizing effect of cyclosporin A on an intrinsic multidrug-resistant rat colon tumour

Colon tumours are intrinsically resistant to chemotherapy and most of them express the multidrug transporter P glycoprotein (Pgp). Whether this Pgp expression determines their resistance to anticancer agents in patients is not known. We report here on the reversibility of intrinsic multidrug resistance in a syngeneic, solid tumour model. CC531 is a rat colon carcinoma that expresses Pgp, as was shown with the monoclonal antibody C-219. In vitro the sensitivity to doxorubicin, daunorubicin and colchicine was enhanced by the addition of the chemosensitizers verapamil and cyclosporin A (CsA), while the sensitivity to cisplatin was not enhanced. In a daunorubicin accumulation assay verapamil and CsA enhanced the daunorbicin content of CC531 cells. In vivo CsA was injected intramuscularly for 3 consecutive days at a dose of 20 mg kg-1 day-1. This resulted in whole-blood CsA levels above 2 μmol/l, while intratumoral CsA levels amounted to 3.6 μmol/kg. In a subrenal capsule assay the maximal tolerable dose of doxorubicin (4 mg/kg) significantly reduced tumour growth. Doxorubicin at 3 mg/kg was not effective, but in combination with CsA this dose was as effective as 4 mg/kg doxorubicin. These experiments show that adequate doses of the chemosensitizing drug CsA can be obtained in vivo, resulting in increased antitumoral activity of doxorubicin in vivo. The in vitro and in vivo data together suggest that the chemosensitization by CsA is mediated by Pgp. This finding may have implications for the application of CsA and CsA-like chemosensitizers in the clinical setting

Drug resistance in rat colon cancer cell lines is associated with minor changes in susceptibility to cytotoxic cells

The development of resistance to anticancer drugs urges the search for different treatment modalities. Several investigators have reported the concomitant development of drug resistance and resistance to natural killer (NK), lymphokine-activated killer (LAK) or monocyte/macrophage cell lysis, while others described unchanged or even increased susceptibility. We investigated this subject in the rat colon carcinoma cell line, CC531-PAR, which is intrinsically multidrug-resistant (MDR), and in three sublines derived from this parental cell line: a cell line with an increased MDR phenotype (CC531-COL), a revertant line from CC531-COL (CC531-REV), which demonstrates enhanced sensitivity to anticancer drugs of the MDR phenotype, and an independently developed cisplatin-resistant line (CC531-CIS). In a 4-h51Cr-release assay we found no difference in susceptibility to NK cell lysis. No significant differences in lysability by adherent LAK (aLAK) cells were observed in a 4-h assay. In a prolonged 20-h51Cr-release assay an enhanced sensitivity to aLAK-cell-mediated lysis was observed in the revertant, P-glycoprotein-negative cell line and in the cisplatin-resistant cell line (CC531-CIS). None of the cell lines was completely resistant to lysis by aLAK cells. Therefore, a role for immunotherapy in the treatment of drug-resistant tumors remains a realistic option

Phase II study of elliptinium in metastatic soft tissue sarcoma

A phase II study was carried out with 9-hydroxy-methyl-elliptinium (9-HME) in metastatic soft tissue sarcoma. The dose was 100 mg/m2 weekly in 1 1 2 hr intravenous infusion protected from light. Nineteen cases were evaluable for response, all previously treated with other chemotherapy regimens. No remissions were seen. Major toxicities were nausea and vomiting, dryness of the mouth and anorexia. It is concluded that 9-HME is not an effective drug in metastatic soft tissue sarcoma. © 1985.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Interactions entre le carboplatine, le cisplatine et les rayonnements ionisants dans une lignée cellulaire humaine de cancer ovarien

© Elsevier, Aim of the study. - Cisplatin (CDDP) and radiotherapy are freqi.ently used concomitantly in the treatment of various malignant conditions. Because of its toxicity, cisplatin tends to be replaced by carboplatin (CBDCA) in several indications. Available data regarding the combined effects of cisplatin and carboplatin with ionising radiation are contradictory. Materials and methods. - Various concentrations of cisplatin and carboplatin and various timing of association with radiation have been tested in vitro in a human ovarian cancer cell line. The parental cell line (AOvC-0) and a cisplatin-resistant stable subline (AOvC-CDDP/0) (De Pooler et al., Cane Res, 1991 ) were exposed to carboplatin (2.5, 5 and 10 M) and to CDDP (1, 2.5 and 5 M), 16h and 4h before and 4h and 16h after irradiation, respectively. Cell survival was evaluated by a classical clonogenic assay. Results. - Exposure of AOvC-0 to 5 M CBDCA and of AOvC-CDDP/0 to 10 M CBDCA, before or shortly after radiation exposure, increased cell lethality in a clear supra-additive way, with the highest DEF in the shoulder region of the survival curve and at radiation doses relevant to clinical radiotherapy. In the sensitive eel! line, 5 M carboplatin resulted in an additional lethality equivalent to 4.5 Gy ; in the resistant cells, 10 M carboplatin was equivalent to 3.6 Gy. Replacing carboplatin by cisplatin in an identical set-up demonstrated exclusively simple additivity (DEF = 1). Conclusion. - These data suggest that carboplatin and cisplatin delivered at equitoxic doses interact with radiation in a different way and that, in the present set-up, only carboplatin enhanced the effects of radiation. Carboplatin might consequently be a better candidate than cisplatin in some concomitant combinations with radiotherapy. © 1999, Elsevier,

Determination of the underivatized antineoplastic drugs cyclophosphamide and 5-fluorouracil and some of 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