Tolyporphin : A natural product from cyanobacteria with potent photosensitizing activity against tumor cells in vitro and in vivo

• Published in: Cancer research (Chicago, Ill.) Vol. 58; no. 16; pp. 3571 - 3578
• Main Authors: MORLIERE, P, MAZIERE, J.-C, SANTUS, R, SMITH, C. D, PRINSEP, M. R, STOBBE, C. C, FENNING, M. C, GOLBERG, J. L, CHAPMAN, J. D
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-08-1998
• Subjects: Animals; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Biological and medical sciences; Coenzyme A-Transferases - drug effects; Coenzyme A-Transferases - metabolism; Cyanobacteria; Cyanophyta; Dihematoporphyrin Ether - therapeutic use; Drug Screening Assays, Antitumor; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Mice; Mice, SCID; Photochemotherapy; Photoradiation therapy and photosensitizing agent; Photosensitizing Agents - pharmacokinetics; Photosensitizing Agents - therapeutic use; Porphyrins - pharmacokinetics; Porphyrins - therapeutic use; Treatment with physical agents; Treatment. General aspects; Tumor Cells, Cultured - drug effects; Tumors; Antineoplastic agent; Animal model; Photodynamic therapy; Toxicity; Treatment efficiency; Rodentia; Malignant tumor; In vitro; Mammary gland diseases; In vivo; Vertebrata; Mammalia; Treatment; Mouse; Porphyrin; Animal; Cyanobacteria; Distribution; Bacteria; Mammary gland; Pharmacokinetics; Photosensitizer; Tumor cell
• ISSN: 0008-5472; 1538-7445

Tolyporphin (TP), a porphyrin extracted from cyanobacteria, was found to be a very potent photosensitizer of EMT-6 tumor cells grown both in vitro as suspensions or monolayers and in vivo in tumors implanted on the backs of C.B17/Icr severe combined immunodeficient mice. Thus, during photodynamic treatment (PDT) of EMT-6 tumor cells in vitro, the photokilling effectiveness of TP measured as the product of the reciprocal of D50 (the light dose necessary to kill 50% of cells) and the concentration of TP is approximately 5000 times higher than that of Photofrin II (PII), the only PDT photosensitizer thus far approved for clinical trials. TP almost exclusively localizes in the perinuclear region and specifically in the endoplasmic reticulum (ER), as shown by microspectrofluorometry on single living EMT-6 cells costained with the ER and/or Golgi fluorescent vital probes, 3,3'-dihexyloxacarbocyanine iodide and N-[4,4-difluoro-(5,7-dimethyl-BODIPY)-1-pentanoyl]-D-erythro-sphin gosine (Molecular Probes, Eugene, OR). As a result, the singlet oxygen-mediated photodynamic activity of TP induces an effective inactivation of the acyl CoA:cholesterol-O-acyltransferase, a sensitive marker of ER membrane integrity and alterations of the nuclear membrane. In vivo, with the EMT-6 mouse tumor model, an exceptional effectiveness is also observed as compared to that of PII and other second generation photosensitizers of the pheophorbide class, which are themselves much more potent than PII. The outstanding PDT activity of TP observed in vivo may be due to its unique biodistribution properties, in particular much less extraction by the liver, resulting in a higher delivery to other tissues, including tumor.