Phototherapy of cancer and atheromatous plaque with texaphyrins.

Cancer and cardiovascular disease are the leading causes of death in the western world. Photodynamic therapy (PDT) has demonstrated activity in the treatment of superficial cancerous lesions and as an intraoperative adjunct during surgical debulking. Texaphyrins are pure, synthetic water-soluble macrocycles that localize in both cancerous lesions and atheromatous plaque. Lutetium texaphyrin (PCI-0123) is activated by tissue-penetrating far red light (720-760 nm). Patient diagnosis and treatment planning is possible via magnetic resonance imaging (MRI) with the paramagnetic gadolinium texaphyrin (PCI-0120) or via fluorescence imaging using the diamagnetic PCI-0123. In this study it is shown that texaphyrins localize selectively in cancer and atheromatous plaque. PDT with PCI-0123 is found to cause selective photodamage to the diseased tissue. Specifically, PCI-0123 acts to eradicate the SMT-F murine mammary tumors and diet-induced atheromatous plaque in rabbits.

Intracellular localization of a chalcogenapyrylium dye probed by spectroscopy and sites of photodamage.

Site(s) of intracellular localization of a photosensitizing chalcogenapyrylium dye were assessed using murine leukemia cells in culture. While the dye exhibited substantial dark toxicity, additional damage was elicited by irradiation. The fluorescence emission spectrum of intracellular dye suggests an initial moderately hydrophobic site of localization (dielectric constant approx. 20). This might represent a membrane interface. But longer incubations led to alterations in both fluorescence emission and absorbance spectra, indicative of both dye migration to a more hydrophilic cellular site and dye biotransformations. Dye-induced cytotoxicity, in either light or dark, was associated with mitochondrial, rather than membrane damage.

Fast atom bombardment mass spectrometry of high-molecular-weight fraction of porphyrin-based photodynamic therapy drugs.

Photodynamic therapy (PDT) involves the treatment of tumor tissue with a photosensitizer and light to effect the delineation and/or eradication of the tumor. PDT is a two step process: (1) incorporation of photosensitizer into the cell where it must be retained by tumors in vivo; and (2) illumination of the tumor cell with light to effect cell death. Hematoporphyrin derivative (HPD) is a complex mixture of porphyrins currently used for PDT in the clinical setting. Hematoporphyrin-based oligomers of up to five subunits were determined using fast atom bombardment mass spectrometry of the high-molecular-weight fraction of the drug. Reduction of this fraction with LiAlH4 permitted determination of the covalent bond linking the monomers in these oligoporphyrins. Application of these analytical procedures to the determination of the composition of different preparations of HPD will be described.

Photosensitization of leukemia L1210 cells with diaziquone.

Exposure of leukemia L1210 cells in culture to the drug diaziquone resulted in inhibition of incorporation of labeled thymidine into nucleic acid and loss of cell viability. These effects were markedly potentiated by irradiation of cells previously exposed to diaziquone in culture. This result shows that diaziquone can catalyze phototoxicity; the action spectrum of the drug may limit clinical applications of this phenomenon.

Transport and binding of hematoporphyrin derivative and related porphyrins by murine leukemia L1210 cells.

A hematoporphyrin derivative (abbreviated in the literature as "HPD") has been used successfully for phototherapy of tumors in the clinic. The chemical nature of HPD, a complex mixture of porphyrins, is not fully understood. This study was designed to provide an explanation for the superior tumor-localizing ability of HPD. Chromatographic behavior, hydrophobicity, transport, binding, and photosensitizing capacity of different porphyrins were examined and compared. Biological studies were carried out using murine leukemia L1210 cells in vitro. The initial rate of porphyrin uptake was a function of drug hydrophobicity. The most hydrophobic components of HPD were therefore the most potent photosensitizers when irradiation followed a 10-min porphyrin-loading incubation. But these and other hydrophobic porphyrins were readily washed from cells by medium containing serum. Hydrophilic components of HPD were gradually accumulated by L1210 cells via a mode of binding not readily dissociated by washing and appear to be responsible for the preferential affinity of this product for neoplastic cells. A portion of the tightly bound porphyrin could not be dissociated by sodium dodecyl sulfate:polyacrylamide gel electrophoresis but remained bound to a low-molecular weight membrane component.