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Background: The multidrug resistance (MDR) proteins are present in a majority of human tumours. Their activity is important to understand the chemotherapeutic failure. A search for MDR-reversing compounds was conducted among various Betti-base derivatives of tylosin.Methods: Here, we evaluate the in vitro and in vivo P-glycoprotein (P-gp)-modulating activity of the most promising compound N-tylosil-1-alpha-amino-(3-bromophenyl)-methyl-2-naphthol (TBN) using human MDR1 gene-transfected and parental L5178 mouse lymphoma cell lines.Results: In vitro experiments showed that TBN dramatically increased the P-gp-mediated cellular uptake of the fluorescent substrate rhodamine 123. Similarly, TBN was found to act as a very potent enhancer of the cytotoxicity of doxorubicin on the resistant cell line. We also provide in vivo evidence using DBA/2 mice in support for an increased tumoural accumulation of doxorubicin, without affecting its tissue distribution, resulting in an enhanced antitumoural effect.Conclusion: Our results suggest that TBN is a potent modulator of the P-gp membrane pump and that the compound could be of clinical relevance to improve the efficacy of chemotherapy in MDR cancers. [ABSTRACT FROM AUTHOR]

Background Hypericin, originating from Hypericum perforatum, is a potent photosensitizer known to induce skin phototoxicity when given systemically. Previously, we have examined the penetration and distribution of hypericin and its acetate ester in the skin of hairless mice after topical application. Objectives In this study, we assessed the time course and skin histopathology of the phototoxic response after a single topical application of hypericin and hypericin acetate, and subsequent irradiation. The amount of blood-borne photosensitizer and the skin clearance, as well the remaining photosensitizing capacity as a function of time, were evaluated. Furthermore, elicited phototoxic responses were compared with those after application of methyl aminolaevulinic acid (Me-ALA). Methods At different time points after topical application of hypericin (0·1–1%) and hypericin acetate (0·015–1·5%) onto mouse ears, penetration and retention of hypericin were assessed by fluorescence microscopy. After definite application times, the ears were irradiated (10 J cm−2, 20 mW cm−2). Ear thickness measurements were conducted daily, and frequently ear samples were taken for histological analysis. Results Application of hypericin on mouse ears resulted only in limited phototoxicity, probably due to confined penetration into the epidermal layers. Extended penetration achieved by administration of hypericin acetate did give rise to a more severe and prolonged response after irradiation, characterized by intense erythema and ear swelling. Skin damage induced by 0·15% hypericin acetate application completely healed in 14 days without scar formation. After a single application of hypericin acetate, the residual photosensitizing capacity was found to decline quickly and was hardly detectable after 7 days. Under the experimental conditions used, hypericin acetate induced equal or more severe phototoxic responses compared with Me-ALA, depending on the concentration. Conclusions Our results indicate that hypericin is an effective photosensitizer not only after systemic administration, but also after topical application, especially when applied as its precursor acetate ester. Moreover, our data provide some insights on safety limits and the time course of skin phototoxicity following hypericin and hypericin acetate application. These data will aid in developing protocols for future photodynamic therapy in the dermatological clinic. [ABSTRACT FROM AUTHOR]

Hypericin is a potent agent in the photodynamic therapy of cancers. To better understand its tumoritropic behaviour, we evaluated the major determinants of the accumulation and dispersion of hypericin in subcutaneously growing mouse tumours. A rapid exponential decay in tumour accumulation of hypericin as a function of tumour weight was observed for each of the six tumour models investigated, and a similar relationship was found between tumour blood flow and tumour weight. Moreover, there was a close correlation between the higher hypericin uptake in RIF-1 tumours compared to R1 tumours and tumour vessel permeability. To define the role of lipoproteins in the transport of hypericin through the interstitial space, we performed a visual and quantitative analysis of the colocalisation of hypericin and DiOC18-labelled lipoproteins in microscopic fluorescent overlay images. A coupled dynamic behaviour was found early after injection (normalised fluorescence intensity differences were on the whole less than 10%), while a shifted pattern in localisation of hypericin and DiOC18 was seen after 24?h, suggesting that during its migration through the tumour mass, hypericin is released from the lipoprotein complex. In conclusion, we were able to show that the tumour accumulation of hypericin is critically determined by a combination of biological (blood flow, vessel permeability) and physicochemical elements (affinity for interstitial constituents).British Journal of Cancer (2005) 92, 1406-1413. doi:10.1038/sj.bjc.6602512 www.bjcancer.com [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is a treatment option particularly well-suited for superficial (pre)malignant skin lesions due to the skin's accessibility to light. In the present study, the efficacy of topical hypericin-PDT was evaluated using a mouse model for actinic keratosis. For comparison, similar experiments were conducted with methyl-aminolevulinic acid (Me-ALA). Small skin tumours (1-2 mm) were induced in hairless mice by chronic UV irradiation. After topical application of hypericin (0.1% in gelcream for 24 h) or Me-ALA (Metvix® for 4 h), the lesional/non-lesional skin surface fluorescence ratio was determined and fluorescence microscopy was used to study the skin penetration of the photosensitizers. The antitumour activity of topical PDT (20 mW cm(-2), 40 J cm(-2)) was evaluated by measurement of the lesional diameters. Moreover, biopsies were taken at various time points after PDT for histological evaluation of the therapy. Our results demonstrate that after topical application of hypericin and Me-ALA, tumour selectivity is limited in mouse skin. The microscopic distribution of hypericin fluorescence showed an accumulation in the stratum corneum and low fluorescence levels in the rest of the lesions, whereas the distribution of PpIX in the skin was more homogenous. Topical hypericin-PDT was found to be less efficient (44% total lesional clearance) as compared to Me-ALA-PDT (80% total lesional clearance). Full lesional necrosis was observed in responsive lesions, and the atypical cells of actinic keratosis were replaced by normal keratinocytes 3 weeks later, both after hypericin-PDT and Me-ALA-PDT., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: To determine the use of hypericin instillation for the fluorescent detection of papillary bladder cancer and carcinoma in situ., Patients and Methods: Eighty-seven patients with papillary bladder cancer and/or carcinoma in situ received instillations with 40 mL of an 8 micromol/L hypericin solution for at least 2 h. Fluorescent excitation with blue light was effective for up to 16 h, and biopsies were examined by fluorescence microscopy., Results: There were no side-effects reported, no photobleaching and all papillary lesions fluoresced red. The sensitivity and specificity for detecting carcinoma in situ was 94% and 95%, respectively. An interval of 4 months is recommended after BCG instillations before using this test. Fluorescence microscopy showed that hypericin was selectively localized in the epithelium., Conclusions: Hypericin-induced fluorescence has a high sensitivity and specificity for detecting bladder cancer. After 4 months there are few false-positive results in patients treated with BCG.