Laser augmented by brachytherapy versus laser alone in the palliation of adenocarcinoma of the oesophagus and cardia: a randomised study

Background: Many patients with advanced malignant dysphagia are not suitable for definitive treatment. The best option for palliation of dysphagia varies between patients. This paper looks at a simple technique for enhancing laser recanalisation. Aim: To assess the value of adjunctive brachytherapy in prolonging palliation of malignant dysphagia by endoscopic laser therapy. Patients: Twenty two patients with advanced malignant dysphagia due to adenocarcinoma of the oesophagus or gastric cardia, unsuitable for surgery or radical chemoradiotherapy. Methods: Patients able to eat a soft diet after laser recanalisation were randomised to no further therapy or a single treatment with brachytherapy (10 Gy). Results were judged on the quality and duration of dysphagia palliation, need for subsequent intervention, complications, and survival. Results: The median dysphagia score for all patients two weeks after initial treatment was 1 (some solids). The median dysphagia palliated interval from the end of initial treatment to recurrent dysphagia or death increased from five weeks (control group) to 19 weeks (brachytherapy group). Three patients had some odynophagia for up to six weeks after brachytherapy. There was no other treatment related morbidity or mortality. Further intervention was required in 10 of 11 control patients (median five further procedures) compared with 7/11 brachytherapy patients (median two further procedures). There was no difference in survival (median 20 weeks (control), 26 weeks (brachytherapy)). Conclusions: Laser therapy followed by brachytherapy is a safe, straightforward, and effective option for palliating advanced malignant dysphagia, which is complementary to stent insertion

Reversal of doxorubicin resistance in breast cancer cells by photochemical internalization

Multiple drug resistance (MDR) is a problem that seriously reduces the efficacy of many chemotherapy agents. One mechanism for MDR is increased acidification of endocytic vesicles and increased cytosol pH, so weak base chemotherapeutic agents, including doxorubicin, are trapped in endocytic vesicles and exhibit a drug resistant phenotype. Treatments that selectively reverse this accumulation may therefore reverse the MDR phenotype. Photochemical internalization (PCI) is a novel technology developed for site-specific enhancement of the therapeutic efficacy of macromolecules by selective photochemical rupture of endocytic vesicles and consequent release of endocytosed macromolecules into the cytosol. This study evaluates PCI for release of doxorubicin from endocytic vesicles in MDR cells. Two breast cancer cell lines, MCF-7 and MCF-7/ADR (the latter resistant to doxorubicin), were selected. They were found equally sensitive to photochemical treatment with the photosensitiser TPPS(2a) (disulfonated meso-tetraphenylporphine) and light. On exposure to doxorubicin alone, the IC(50) (drug concentration for 50% reduction in colony formation) was 0.1 mu M for MCF-7 and 1 mu M for MCF-7/ADR. After PCI (photochemical treatment followed by doxorubicin), the IC(50) concentration was 0.1 mu M for both cell lines. Comparable changes were seen with assay of cell viability using 3-(4,5-dime- thyltiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). On fluorescence microscopy in MCF-7/ADR cells, doxorubicin localised in granules identified as lysosomes. After PCI, doxorubicin was released into the cytosol and entered cell nuclei, as was seen in MCF-7 cells without PCI. In conclusion, PCI reversed the MDR phenotype of doxorubicin resistant breast cancer cells by endo-lysosomal release of the drug. The technique is a promising new approach to tackling the problem of MDR. (c) 2006 Wiley-Liss, Inc