Low-density lipoprotein receptors in the uptake of tumour photosensitizers by human and rat transformed fibroblasts

Polo, Luz; Valduga, Giuliana; Jori, Giulio; Reddi, Elena

doi:10.1016/s1357-2725(01)00092-9

Cited by 91 publications

(69 citation statements)

References 42 publications

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“…High drug levels in organs of the reticuloendothelial system, e.g., liver and spleen, were likely associated with macrophage accumulation of Photofrin, as has been reported by others (12,13). Moderately high Photofrin content in the isolated mucosal layer of both the large and small intestine could perhaps be a consequence of residual fecal matter on this surface after the gross removal of material by handheld instruments and rinsing (14); additionally, the intestinal lining contains high numbers of low-density lipoprotein receptors (15,16), which have been shown to mediate photosensitizer uptake (17,18). Substantial Photofrin content in the appendix might also be explained by presence of digestive matter.…”

Section: Discussionmentioning

confidence: 99%

Photofrin Uptake in the Tumor and Normal Tissues of Patients Receiving Intraperitoneal Photodynamic Therapy

Hahn

Putt²,

Metz

et al. 2006

Clinical Cancer Research

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Purpose: A phase II trial of Photofrin-mediated i.p. photodynamic therapy shown in a previous report limited efficacy and significant acute, but not chronic, toxicity. A secondary aim of this trial and the subject of this report is to determine Photofrin uptake in tumor and normal tissues. Experimental Design: Patients received Photofrin, 2.5 mg/kg, i.v., 48 hours before debulking surgery. Photofrin uptake was measured by spectroflurometric analysis of drug extracted from tumor and normal tissues removed at surgery. Differences in drug uptake among these tissues were statistically considered using mixed-effects models. Results: Photofrin concentration was measured in 301samples collected from 58 of100 patients enrolled on the trial. In normal tissues, drug uptake significantly (P < 0.0001) differed as a function of seven different tissue types. In the toxicity-limiting tissue of intestine, the model-based mean (SE) Photofrin level was 2.70 ng/mg (0.32 ng/mg) and 3.42 ng/mg (0.24 ng/mg) in full-thickness large and small intestine, respectively. In tumors, drug uptake significantly (P = 0.0015) differed as a function of patient cohort: model-based mean Photofrin level was 3.32 to 5.31ng/mg among patients with ovarian, gastric, or small bowel cancer; 2.09 to 2.45 ng/mg among patients with sarcoma and appendiceal or colon cancer; and 0.93 ng/mg in patients with pseudomyxoma. Ovarian, gastric, and small bowel cancers showed significantly higher Photofrin uptake than full-thickness large and/or small intestine. However, the ratio of mean drug level in tumor versus intestine was modest (V2.31). Conclusions: Some selectivity is found in Photofrin uptake between tumor and normal tissues of the peritoneal cavity, but absolute differences in drug uptake relative to toxicity-limiting normal tissues (intestine) are small. This narrow differential in drug selectivity likely contributes to a narrow window in therapeutic application, which has been previously reported.

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Section: Discussionmentioning

confidence: 99%

Photofrin Uptake in the Tumor and Normal Tissues of Patients Receiving Intraperitoneal Photodynamic Therapy

Hahn

Putt²,

Metz

et al. 2006

Clinical Cancer Research

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“…Those investigated by us in early (18,19) and in the present studies have the peculiarity to contain the organometallic moieties bonded to the oxygen atoms of the side chain sulfonatophenyl groups of a porphyrin ring. Porphyrins are well-known to have a clear tendency to localize tumour by means of low-density lipoproteins (LDL), whose specific receptors are highly expressed in many types of transformed cells (32).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis and cell growth arrest in A375 human melanoma cells by diorganotin(IV) and triorganotin(IV) complexes of [meso-Tetra(4-sulfonatophenyl)porphine] manganese(III)chloride

Costa

Zito

Emma³

et al. 2011

Int J Oncol

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Abstract.In previous studies we have demonstrated that two derivatives of meso-Tetra(4-sulfonatophenyl)porphine (TPPS), (Bu 2 Sn) 2 TPPS and (Bu 3 Sn) 4 TPPS, cause apoptotic death of A375 melanoma cells and, at lower concentrations, arrest of cell proliferation. In the present study, we examined if the manganese metal inside the porphyrin cavity could improve the efficacy of this class of compounds. Thus, [mesoTetra(4-sulfonatophenyl)porphine]Mn(III)Cl (=MnTPPS) derivatives, namely (Me 2 Sn) 2 MnTPPS, (Bu 2 Sn) 2 MnTPPS, (Me 3 Sn) 4 MnTPPS and (Bu 3 Sn) 4 MnTPPS, were tested on the A375 human melanoma cell line. A cytotoxicity assay showed that (Bu 2 Sn) 2 MnTPPS and (Bu 3 Sn) 4 MnTPPS were highly cytotoxic by inducing apoptosis in melanoma cells, as shown by DNA fragmentation analysis and by apoptotic nuclei fluorescence, and when used at lower concentrations, they affected only cellular proliferation. An arrest of cell proliferation was also observed with (Me 3 Sn) 4 MnTPPS, but at the highest concentrations used. Moreover, the lower concentration of (Bu 3 Sn) 4 MnTPPS induced a change in cell morphology, from a polygonal to an elongated and spindleshaped phenotype, likewise to its cognate (Bu 3 Sn) 4 TPPS, previously tested. Western blotting analysis showed indeed that both tributyltin compounds, i.e. (Bu 3 Sn) 4 MnTPPS and (Bu 3 Sn) 4 TPPS, lowered levels of the major proteins involved in tumorigenesis: ß-catenin, c-myc and snail. We also demonstrated that all compounds entered the cells and localized in the nuclei. In conclusion, our results show that, in spite of the Mn(III) metal introduction, the butyl derivatives always have a higher efficacy than methyl derivatives, and the tributyltin compounds in particular have an interesting effect in vitro on A375 cell proliferation.

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“…injection frequently relies upon leukocytes and lipoproteins as drug carriers [Polo et al, 2002;Konan et al, 2002;Derycke et al, 2004] and the suppression of this pathway in the case of a gel should lead to milder side effects. Although nude mice have immunological and microvascular differences from humans, the distinct biodistribution of TPP and PC absorbed from a gel is likely to be confirmed during possible future clinical studies.…”

Section: Discussionmentioning

confidence: 99%

“…This is caused by poor lymphatic drainage, leaky vasculature, acidic pH, increased low-density lipoprotein (LDL) receptors, and abnormal stroma composition of tumors. The LDL pathway may be facilitated by liposomal formulations of photosensitizers [Polo et al, 2002]. Various types of delivery systems have been proposed as carriers for improving the selectivity of antitumor drugs [Konan et al, 2002], especially porphyrin-based photosensitizers, including monoclonal antibodies [Rahimipour et al, 2003], liposomes [Cuomo et al, 1990;Love et al, 1996;Ježek et al, 2003;Konan et al, 2002;Derycke et al, 2004;Kepczynski et al, 2006;Sadzuka et al, 2006], microspheres and nanoparticles [Yan and Kopelman, 2003;Roy et al, 2003;Ricci and Marchetti, 2006], growth factors, hormones, and LDLs [Polo et al, 2002].…”

mentioning

confidence: 99%

Optimum modality for photodynamic therapy of tumors: gels containing liposomes with hydrophobic photosensitizers

Nekvasil

Zadinová

Tahotná

et al. 2007

Drug Development Research

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Photodynamic therapy (PDT) has entered an era of clinical acceptance; however, for its wider use, including drug formulations for topical applications, it must have a rapid effect and be free of skinphotosensitization effects. Preclinical studies of two prototype formulations exhibiting successful therapeutic rates based on translucent gels containing liposomes with hydrophobic photosensitizers are presented. Experimental PDT of human tumors implanted in nude mice with liposomal gels containing meso-tetrakisphenylporphyrin (TPP) or hydroxy-aluminum phthalocyanine (PC) caused significant dystrophy of human basal cell carcinoma, amelanotic melanoma, breast carcinoma, and colorectal carcinoma. Whereas the drug-to-light time interval for TPP was 12 h, much less than that of most commercially available approved photosensitizers, 10 min was sufficient to disintegrate the effects of the PC liposomal gel. Liposomes containing hydrophobic photosensitizers were prepared either by extrusion through 100-nm filters or using a microfluidizer. Histology of tumors in remission showed existence of overall necrosis and the presence of only small islets of tumorous cells in incomplete remission. Fibrinoid necrosis of the tumors was a visible sign of the therapeutic effect. TPP and PC from the gel were distributed by circulation to the organs and tissues in a different and more favorable pattern than by intravenous injection. We conclude that hydrophobic photosensitizers are preferable and more efficient for PDT (Ježek et al., Int J Cancer 103:693-702, 2003) and their liposomal gel formulations are predicted to be optimum preparations enabling wide ranging use of topical PDT for numerous cancer indications, initially for nonmelanoma skin cancer. Drug Dev Res 68: [235][236][237][238][239][240][241][242][243][244][245][246][247][248][249][250][251][252] 2007 r 2007 Wiley-Liss, Inc.

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Low-density lipoprotein receptors in the uptake of tumour photosensitizers by human and rat transformed fibroblasts

Cited by 91 publications

References 42 publications

Photofrin Uptake in the Tumor and Normal Tissues of Patients Receiving Intraperitoneal Photodynamic Therapy

Photofrin Uptake in the Tumor and Normal Tissues of Patients Receiving Intraperitoneal Photodynamic Therapy

Apoptosis and cell growth arrest in A375 human melanoma cells by diorganotin(IV) and triorganotin(IV) complexes of [meso-Tetra(4-sulfonatophenyl)porphine] manganese(III)chloride

Optimum modality for photodynamic therapy of tumors: gels containing liposomes with hydrophobic photosensitizers

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