Modulation of P-glycoprotein-mediated multidrug resistance in the CC531 rat colon tumor model

About half of the patients that come to the physician with cancer have a localized stage of the disease and can be cured by surgery or radiotherapy. The remaining cancers have spread systemically because the primary tumor has metastasized or because they are systemic cancers by nature. The only hope for cure for patients with these cancers lies in systemic treatment such as chemotherapy or immunotherapy. Cure can be obtained by intensive chemotherapy in childhood acute leukemia and sarcoma, in adult testicular cancer and choriocarcinoma, and, to a lesser extent, in lymphomas. In other malignancies like breast cancer adjuvant chemotherapy after curative surgical ablation has proven beneficial in a minority of the patients by reducing the likelihood of disease recurrence. In these patients residual microscopic disease, which would have resulted in disease recurrence, has been eradicated by chemotherapy. However, only 5%-10% of the patients with systemic cancer can be cured by chemotherapy to day.l,2 A still much smaller percentage of the cancers responds to various forms of immunotherapy

The chemosensitizer cyclosporin A enhances the toxic side-effects of doxorubicin in the rat

the feasibility of using chemosensitizers in the circumvention of P-glycoprotein-mediated multidrug resistance has been shown in many studies. We recently reported on the chemosensitizing effect of cyclosporin A (CsA) on doxorubicin in a rat solid tumour model. Using the same experimental design we investigated the side-effects of the combination treatment. During the 35-day experiment doxorubicin treatment caused dose-dependent weight loss, which was enhanced by combination treatment with CsA. The main doxorubicin-related side-effects were myelosuppression (transient leucopenia and thrombopenia) and nephrotoxicity. Damage to the kidney was severe, leading to a nephrotic syndrome and resulting in ascites, pleural effusion, hypercholesterolaemia and hypertriglyceridaemia. These toxicities were enhanced by the addition of the chemosensitizer CsA. Mild doxorubicin-related cardiomyopathy and minimal hepatotoxicity were seen on histological examination. There were no signs of enhanced toxicity of the combination treatment in tissues with known high expression levels of P-glycoprotein, like the liver, adrenal gland and large intestine. CsA had a low toxicity profile, as it only caused a transient rise in bilirubin. In conclusion, the chemosensitizer CsA enhanced the side-effects of the anticancer drug doxorubiein without altering the toxicity pattern. There was no evidence of a therapeutic gain by adding CsA to doxorubicin, compared to single-agent treatment with doxorubicin in 25%-33% higher doses, because of the enhanced toxicity of the combination treatment

Development of the Nurses' Observation Scale for Cognitive Abilities (NOSCA)

Background. To assess a patient's cognitive functioning is an important issue because nurses tailor their nursing interventions to the patient's cognitive abilities. Although some observation scales exist concerning one or more cognitive domains, so far, no scale has been available which assesses cognitive functioning in a comprehensive way. Objectives. To develop an observation scale with an accepted level of content validity and which assesses elderly patients' cognitive functioning in a comprehensive way. Methods. Delphi technique, a multidisciplinary panel developed the scale by consensus through four Delphi rounds (>70% agreement). The International Classification of Functioning/ICF was used as theoretical framework. Results. After the first two Delphi rounds, the panel reached consensus about 8 cognitive domains and 17 sub domains. After two other rounds, 39 items were selected, divided over 8 domains and 17 sub domains. Discussion. The Nurses' Observation Scale Cognitive Abilities (NOSCA) was successfully designed. The content validity of the scale is high because the scale sufficiently represents the concept of cognitive functioning: the experts reached a consensus of 70% or higher on all domains and items included; and no domains or items were lacking. As a next step, the psychometric qualities of the NOSCA will have to be tested

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

High renin and prorenin in plasma and pleural exudate of a patient with the ovarian hyperstimulation syndrome

We present the case of a 35-year-old woman with a severe ovarian hyperstimulation syndrome (OHSS) as a complication of ovulation induction for primary infertility. The clinical picture showed massively enlarged ovaries, pleural effusion and haemoconcentration. She needed a thoracentesis for evacuation of the large pleural effusion. High levels of renin and prorenin were observed in plasma and pleural exudate

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

In situ light dosimetry during photodynamic therapy of Barrett's esophagus with 5-aminolevulinic acid

Background and Objectives: Previous studies with PhotoDynamic Therapy (PDT) in bladder and bronchi have shown that due to scattering and reflection, the actually delivered fluence rate on the surface in a hollow organ can be significantly higher than expected. In this pilot study, we investigated the differences between the primary calculated and the actual measured fluence rate during PDT of Barrett's Esophagus (BE) using 23 independent clinical measurements in 15 patients. Study Design/Materials and Methods: A KTP-dye module laser at 630 nm was used as light source. Light delivery was performed using a cylindrical light diffuser inserted in the center of an inflatable transparent balloon with a length corresponding to the length of the Barrett's epithelium. The total light output power of the cylindrical diffuser was calibrated using an integrating sphere to deliver a primary fluence rate of 100 mW cm-2. Two fiber-optic pseudo sphere isotropic detectors were placed on the balloon and were used to measure fluence rate at the surface of the esophageal wall during PDT. Results and Conclusions: The actual fluence rate measured was 1.5-3.9 times higher than the primary fluence rate for 630 nm. In general, the fluence rate amplification factor decreased with increasing redness of the tissue and was less for shorter diffusers. Fluence rate variations in time were observed which coincided with patients coughing, movement, and esophageal spasms. These factors combined with inter patient variability of the fluence rate measured appears to justify the routine application of this technique in PDT of BE

Modulation of multidrug resistance with dexniguldipine hydrochloride (B8509-035) in the CC531 rot colon carcinoma model

The chemosensitizing potency of dexniguldipine hydrochloride (B8509-035) on epidoxorubicin was assessed in a multidrug-resistant (MDR) tumour model, the intrinsic MDR rat colon carcinoma CC531. In vitro in the sulphorhodamine B cell-viability assay the cytotoxicity of epidoxorubicin was increased approximately 15-fold by co-incubation with 50 ng/ml dexniguldipine. In vivo concentrations of dexniguldipine 5 h after a single oral dose of 30 mg/kg were 72 (± 19 SD) ng/ml in plasma and 925 (± 495 SD) ng/g in tumour tissue. Levels of the metabolite of dexniguldipine, M-1, which has the same chemosensitizing potential, were 26 (± 6 SD) ng/ml and 289 (± 127 SD) ng/g respectively. The efficacy of treatment with 6 mg/kg epidoxorubicin applied intravenously combined with 30 mg kg-1 day-1 dexniguldipine administered orally for 3 days prior to epidoxorubicin injection was evaluated on tumours grown under the renal capsule. Dexniguldipine alone did not show antitumour effects in vivo. Dexniguldipine modestly, but consistently, potentiated the tumour-growth-inhibiting effect of epidoxorubicin, reaching statistical significance in two out of four experiments. In conclusion, these experiments show that dexniguldipine has potency as an MDR reverter in vitro and in vivo in this solid MDR tumour model

Pharmacokinetics of the multidrug-resistance-converting drug dexniguldipine and its pyridine metabolite M-1 in the plasma, tumor, and renal tissue of tumor-bearing Wag/Rij rats

The pharmacokinetics of oral dexniguldipine, a new multidrug-resistance- modifying agent under clinical evaluation, and its pyridine metabolite M-1 were determined in plasma, tumor, and renal tissue in Wag/Rij rats bearing a multidrug-resistant CC531 colon adenocarcinoma tumor under the renal capsule. The pharmacokinetics were studied in four experiments. After a single administration of dexniguldipine (30 mg/kg), tumors and kidneys were collected after 5 (experiment 1), 24 (experiment 2), and 48 h (experiment 3). In the fourth experiment, dexniguldipine was given once daily for 3 consecutive days at a dose of 30 mg/kg. In all experiments, plasma samples were collected at regular intervals. The concentrations of dexniguldipine and M-1 could be determined in plasma in most of the rats at up to 32 h after drug administration. The area under the curve (AUC) of dexniguldipine and M- 1 varied by a factor of 2-6 in the four experiments. High tumor-tissue concentrations of dexniguldipine were observed. The concentrations were highest in the multiple-dose experiment (2014 ± 1005 ng/g tissue). High degrees of correlation (>08) were established between the concentrations of dexniguldipine measured in plasma and tumor as well as renal tissue. Overall, tumor-tissue concentrations of M-1 comprised one-third of the dexniguldipine concentrations measured