talaporfin and Neoplasms

The low-intensity ultrasound that is used in clinical diagnoses, such as abdomen echo inspection, is a non-invasive treatment, and penetrates deeper into the body than light. Recently, sonodynamic therapy (SDT), which uses low-intensity ultrasound together with a sonosensitizer, has been developed for cancer therapy in applying such properties of ultrasound. So far, most sonosensitizers that have been developed are sensitive to light as well as ultrasound, implying that the shortcomings of photosensitizers used during photodynamic therapy, such as skin sensitivity, still need to be overcome in SDT. Some exceptions were, however, reported in recent studies in which sensitizers were activated mainly by ultrasound but not by light. Furthermore, recent in vivo studies have demonstrated that SDT with a sonosensitizer has a great potential as a non-invasive and repeatable treatment for cancer therapy.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Delivery Systems; Genetic Therapy; Humans; Liposomes; Microbubbles; Nanocapsules; Neoplasms; Neoplasms, Experimental; Photochemotherapy; Photosensitizing Agents; Porphyrins; T-Lymphocytes, Cytotoxic; Ultrasonic Therapy; Xenograft Model Antitumor Assays

Despite therapeutic advances, cancer remains the cause of an estimated 23% of deaths in the USA. New treatments for malignancy are greatly needed.. Talaporfin sodium is a light-activated drug that causes tissue death through induction of apoptosis. Systemic antitumor effects mediated by CD8(+) T cells have been demonstrated in preclinical studies, providing a mechanism for distant response of tumors noted in clinical trials. Talaporfin sodium is approved in Japan for early-stage endobronchial cancer. Phase I and II studies in solid tumors have shown tumor regression in patients refractory to other therapies. Phase III pivotal studies against hepatocellular carcinoma as monotherapy and liver-metastatic colorectal cancer in combination with chemotherapy are ongoing. Talaporfin sodium is also in studies in men with symptomatic benign prostatic hyperplasia. Substantial safety data from clinical trials so far indicate that the drug is well tolerated.. Talaporfin sodium has a broad safety profile and a mode of action that could affect growth in treated and untreated tumors.. Clinical and preclinical studies indicate that talaporfin sodium treatment may offer a powerful option to synergize current therapies, as well as an alternative monotherapy in treating cancer.

Topics: Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Cancer Vaccines; Carcinoma, Hepatocellular; Clinical Trials, Phase III as Topic; Colorectal Neoplasms; Combined Modality Therapy; Humans; Japan; Liver Neoplasms; Male; Neoplasm Staging; Neoplasms; Oxides; Porphyrins

The activity of a new photosensitizer, mono-L-aspartyl chlorin e6 (Npe6), was assessed in an ascending dose Phase I study for patients with superficial tumor. Eleven patients, with a total of 14 tumor sites, were treated with photodynamic therapy (PDT) using Npe6. Lesions included recurrent adenocarcinoma of the breast, basal cell carcinoma, and squamous cell carcinoma. The phototherapy protocol consisted of a single i.v. injection of 0.5-3.5 mg/kg Npe6, followed 4 h later by 25-100 j/cm2 at 664 nm of light. PDT using Npe6 caused no significant toxicity with the exception of temporary generalized skin photosensitivity. In all cases, light treatment caused immediate tissue blanching, followed by a marked necrosis of the tumor mass. Regression of tumor occurred over 24-48 h after the light treatment and was followed by the formation of a heavy eschar over the tumor site. Tumor regression was short-lived at Npe6 doses of 1.65 mg/kg and below. In two of three patients, tumor regression was either incomplete or tumors recurred within the 12-week observation period. Increasing the Npe6 dose to 2.5 or 3.5 mg/kg combined with 100 J/cm2 of light energy resulted in better control of tumor regrowth with 66% (6/9) of sites remaining tumor-free through 12 weeks observation. This increased tumor response came at the expense of the tissue selectivity observed at Npe6 doses of 1.65 mg/kg and below. There was no apparent selectivity for destruction of tumor compared with normal skin at Npe6 doses of 2.5 mg/kg and above. These data demonstrate that Npe6 is both an effective and safe photosensitizer for use in PDT and provide the impetus for continued study in Phase II clinical trials.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Dermatitis, Phototoxic; Edema; Erythema; Female; Humans; Male; Middle Aged; Neoplasms; Pain; Photochemotherapy; Photosensitizing Agents; Porphyrins; Treatment Outcome

We proposed the application of photodynamic therapy (PDT) as a new type of atrial fibrillation treatment. PDT is well known as a practical cancer treatment using cytotoxicity of reactive oxygen species generated by the photochemical interaction. We predicted that the photocytotoxic effect induced by PDT might cause electrical blockade in myocardial tissue. We studied the electrical blockade induced by the PDT with talaporfin sodium in vitro, ex vivo, and in vivo. The cell lethality measurement using rat cardiac myocytes confirmed the PDT-induced photocytotoxic effect and its dependence on the loading time of the photosensitizer. In ex vivo experiment using rat right ventricle, the PDT caused a shutdown of the stimulated electrical signal propagation. The long-lasting atrioventricular block induced by the PDT was obtained in vivo experiment with rat heart. These results revealed the possibility of atrial fibrillation treatment with the PDT.

Topics: Animals; Atrial Fibrillation; Atrioventricular Block; Electric Conductivity; Heart; Heart Ventricles; Light; Myocardium; Myocytes, Cardiac; Neoplasms; Photochemistry; Photosensitizing Agents; Porphyrins; Rats; Reactive Oxygen Species

NPe6 is a novel second-generation photosensitizer used for photodynamic therapy (PDT). PDT using NPe6 and diode laser (664 nm) induces cell death, inflammatory reactions, immunological responses and damage to the microvasculature. In this study, we evaluated the influence of the immunological responses and of enhanced angiogenesis on the anti-tumor effect of NPe6-PDT using cytokine-overexpressing Lewis lung carcinoma (LLC), LLC-IL-2 cells both in vitro and in vivo. We showed by DNA microarray analysis in vitro that IL-2 and GADD-45alpha (growth arrest and DNA damage 45 alpha) mRNA expressions were induced by 3 h after NPe6-PDT applied at a dose killing 90% of the cells (LD90). IL-2-overexpressing cells (LLC/IL-2 cells) were resistant to the loss of clonogenicity as compared to the parental LLC cells in vitro. Furthermore, in female C57BL/6 mice, NPe6-PDT produced a cure rate of 66.7% in LLC tumors, whereas the cure rate was only 16.6% in LLC/IL-2 tumors, and overexpression of IL-2 caused failure of NPe6-PDT, with tumor recurrence, in vivo. These results suggest that IL-2 expression may play an unfavorable role in attenuation of the antitumor effect of NPe6-PDT. It has been reported that the expression of vascular endothelial growth factor (VEGF), in particular, may cause tumor recurrence after PDT and exert unfavorable effect in relation to attenuate the anti-tumor activity of PDT. Results of immunohistochemical analysis of LLC/IL-2 tumors have revealed that the expressions of GADD-45alpha and VEGF are induced in these tumors after PDT, and in particular, 12 h after PDT, the expression levels were much higher as compared with those in the LLC tumors. The results of our studies using in vitro and in vivo models suggest that the cell death caused by PDT was inhibited by induction of GADD-45alpha expression and that tumor recurrence was promoted by the enhancement of VEGF expression mediated by IL-2 upregulation. Therefore, it is speculated that the use of an IL-2 inhibitor may improve the efficacy of NPe6-PDT.

Topics: Animals; Carcinoma, Lewis Lung; Cell Cycle Proteins; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Interleukin-2; Mice; Mice, Inbred C57BL; Neoplasms; Nuclear Proteins; Photochemotherapy; Photosensitizing Agents; Porphyrins; Recurrence; Vascular Endothelial Growth Factor A

Photodynamic therapy (PDT) involves the administration of a photosensitizer, followed by local illumination of a tumor with a laser (of the appropriate wavelength) to activate a specific drug. However, the cells in a tumor tissue are heterogeneous, in terms of their morphologies and differentiation statuses, even if the tumor consists of progeny developed from a single neoplastic cell. It is not known how tumor cell heterogeneity affects their sensitivity to PDT. Here, we demonstrate that a single tumor cell has the potential to produce a progeny that is heterogeneous in terms of morphology, VEGF secretion, and PDT sensitivity, irrespective of intracellular photosensitizer amount. Understanding tumor cell heterogeneity for clinical applications of PDT will help in the design of new interventions and potentially improve long-term survival of PDT treated patients.

Topics: Cell Line, Tumor; Humans; Neoplasms; Neoplastic Stem Cells; Photochemotherapy; Porphyrins; Vascular Endothelial Growth Factor A

One of the 'second generation' photosensitizing agents is N-acetyl chlorin e6 (NPe6). This product has a strong absorbance band at 665 nm, permitting treatment at a greater depth of tumor than earlier agents based on porphyrin structures. We examined the effects of fractionated drug administration on photodynamic efficacy. Prior studies had shown that it is the level of NPe6 in the circulation that predicts for photodynamic efficacy, indicating vascular shut-down to be the predominant mode of tumor control. Although pharmacokinetic studies revealed that >99% of NPe6 was lost from the circulation, it appears that a fractionated dosage protocol can promote photodamage to neoplastic tissue in vivo. This study also indicated the potential utility of an implantable micro array for tumor irradiation.

Topics: Analysis of Variance; Animals; Cell Line, Tumor; Female; Humans; Mice; Mice, Inbred C57BL; Neoplasms; Photochemotherapy; Photosensitizing Agents; Porphyrins; Xenograft Model Antitumor Assays

Topics: Animals; Cholangiocarcinoma; Clinical Trials, Phase I as Topic; Drugs, Investigational; Humans; Injections, Intravenous; Neoplasms; Photosensitizing Agents; Porphyrins; Rats; Rats, Sprague-Dawley

Photodynamic therapy (PDT) protocols employing lysosomal sensitizers induce apoptosis via a mechanism that causes cytochrome c release prior to loss of mitochondrial membrane potential (DeltaPsi(m)). The current study was designed to determine how lysosomal photodamage initiates mitochondrial-mediated apoptosis in murine hepatoma 1c1c7 cells. Fluorescence microscopy demonstrated that the photosensitizer N-aspartyl chlorin e6 (NPe6) localized to the lysosomes. Irradiation of cultures preloaded with NPe6 induced the rapid destruction of lysosomes, and subsequent cleavage/activation of Bid, pro-caspases-9 and -3. Pro-caspase-8 was not activated. Release of cytochrome c occurred at about the time of Bid cleavage and preceded the loss of DeltaPsi(m). Extracts of purified lysosomes catalyzed the in vitro cleavage of cytosolic Bid, but not pro-caspase-3 activation. Pharmacological inhibition of cathepsin B, L and D activities did not suppress Bid cleavage or pro-caspases-9 and -3 activation. These studies demonstrate that photodamaged lysosomes trigger the mitochondrial apoptotic pathway by releasing proteases that activate Bid.

Topics: Animals; Apoptosis; BH3 Interacting Domain Death Agonist Protein; Carrier Proteins; Caspase 8; Caspase 9; Caspases; Cathepsin D; Cell Extracts; Cytochrome c Group; Enzyme Inhibitors; Enzyme Precursors; Lysosomes; Mice; Mitochondria; Neoplasms; Photochemotherapy; Porphyrins; Tumor Cells, Cultured

We examined the pharmacokinetics of the photosensitizer N-aspartyl chlorin e6 in a group of cancer patients. While the drug persisted in plasma for as long as six weeks, there was no evidence of fluorescent NPe6 metabolites during this interval. Kinetics of drug elimination from plasma were consistent with a 2-compartment model with half-lives of approximately 9 hr (57%) and 134 hr (43%). The drug was bound to plasma albumin+other heavy proteins (65%) > HDL (35%) > > LDL (1-2%). These relative values did not change for as long as 21 days after drug administration. The long persistence of NPe6 in plasma was not associated with extended skin photosensitization.

Topics: Blood Proteins; Humans; Neoplasms; Photosensitizing Agents; Porphyrins

Most sensitizers used for the photodynamic therapy (PDT) of tumors photobleach on illumination. Thus, it is of interest to examine the photobleaching behavior of new sensitizers proposed for use in PDT. This report surveys the quantum yields and kinetics of the photobleaching of mono-L-aspartyl chlorin e6(NPe6), a hydrophilic chlorin that has many of the photoproperties desirable in a sensitizer for clinical PDT. It is a very effective sensitizer for the PDT of several types of model tumors in animals and is now in Phase I clinical trials. The quantum yield of NPe6 photobleaching in pH 7.4 phosphate buffer in air was 8.2 x 10(-4); this is greater than the yields for typical porphyrin photosensitizers. For example, the yields for hematoporphyrin and uroporphyrin are 4.7 x 10(-5) and 2.8 x 10(-5), respectively. The yield decreased significantly in organic solvents of low dielectric constant. The Sn derivative of NPe6 was more light stable than NPe6 (yield = 5.7 x 10(-6), while the Zn derivative was more sensitive (yield = 1.9 x 10(-2). Oxygen appeared to be necessary for the photobleaching of NPe6; however, bleaching was not inhibited by 100 mM azide, an efficient quencher of singlet oxygen. The photooxidizable substrates cysteine, dithiothreitol and furfuryl alcohol increased the quantum yield of photobleaching two- to four-fold, while the electron acceptor, metronidazole, increased it almost six-fold. Photobleaching yields for several other chlorins were also measured.

Topics: Animals; Antineoplastic Agents; Aspartic Acid; Azides; Deuterium; Humans; Mannitol; Metronidazole; Molecular Structure; Neoplasms; Paraquat; Photochemistry; Photochemotherapy; Photosensitizing Agents; Porphyrins; Solvents