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Catheterization and Cardiovascular... Nov 2002Photodynamic therapy (PDT) has been approved as a tissue-specific light-activated cytotoxic therapy for many diseases. The ability of PDT to destroy target tissues... (Review)
Review
Photodynamic therapy (PDT) has been approved as a tissue-specific light-activated cytotoxic therapy for many diseases. The ability of PDT to destroy target tissues selectively is especially appealing for atherosclerotic plaque. Biotechnology has developed a new generation of selective photosensitizers and catheter-based technological advances in light delivery have allowed the introduction of PDT into the vasculature. The largest experience to date is with motexafin lutetium (MLu, Antrin), an expanded porphyrin (texaphyrin) that accumulates in plaque. The combination of the motexafin lutetium and endovascular illumination, or Antrin phototherapy, has been shown to reduce plaque in animal models. Antrin phototherapy generates cytotoxic singlet oxygen that has been shown to induce apoptosis in macrophages and smooth muscle cells. The safety, tolerability, and preliminary efficacy of Antrin phototherapy has been assessed in a phase 1 dose-ranging clinical trial in subjects with peripheral artery disease and is currently being examined in a phase 1 study in subjects with lesions of the native coronary arteries undergoing stent implantation. The preliminary results suggest that Antrin phototherapy is safe, well tolerated, and nontraumatic.
Topics: Animals; Coronary Artery Disease; Graft Occlusion, Vascular; Humans; Metalloporphyrins; Photochemotherapy; Photosensitizing Agents; Treatment Outcome
PubMed: 12410519
DOI: 10.1002/ccd.10336 -
IDrugs : the Investigational Drugs... Mar 2001Pharmacyclics is developing the photosensitizer, motexafin lutetium as Antrin for the potential treatment of restenosis and atherosclerotic plaques, Lutrin for the...
Pharmacyclics is developing the photosensitizer, motexafin lutetium as Antrin for the potential treatment of restenosis and atherosclerotic plaques, Lutrin for the possible treatment of cancer, and Optrin for the possible treatment of age-related macular degeneration (AMD). ANTRIN: A phase II multicenter, randomized, controlled study involving 375 peripheral artery disease (PAD) patients is being conducted in the US. It is designed to evaluate Antrin photoangioplasty as a primary treatment for PAD and for the prevention of restenosis following balloon angioplasty [341341,347151]. LUTRIN: Lutrin is being developed for the possible treatment of a number of cancers [348919]. In July 1997, the compound entered phase II trials for breast cancer [323952,323929]. In August 2000, the compound was undergoing a phase IIb trial for advanced refractory breast cancer [380234]. OPTRIN: In May 2000, Pharmacyclics reported preliminary results from an ongoing phase II dose-ranging study with Optrin for the photodynamic therapy of patients with AMD [365074].
PubMed: 16025394
DOI: No ID Found -
Clinical Cancer Research : An Official... Aug 2008The time course of serum prostate-specific antigen (PSA) response to photodynamic therapy (PDT) of prostate cancer was measured.
PURPOSE
The time course of serum prostate-specific antigen (PSA) response to photodynamic therapy (PDT) of prostate cancer was measured.
EXPERIMENTAL DESIGN
Seventeen patients were treated in a phase I trial of motexafin lutetium-PDT. PDT dose was calculated in each patient as the product of the ex vivo measured pre-PDT photosensitizer level and the in situ measured light dose. Serum PSA level was measured within 2 months before PDT (baseline), and at day 1; weeks 1 to 3; months 1, 2, and 3; months 4 to 6; and months 7 to 11 after PDT.
RESULTS
At 24 hours after PDT, serum PSA increased by 98% +/- 36% (mean +/- SE) relative to baseline levels (P = 0.007). When patients were dichotomized based on median PDT dose, those who received high PDT dose showed a 119% +/- 52% increase in PSA compared with a 54% +/- 27% increase in patients treated at low PDT dose. Patients treated with high versus low PDT dose showed a median biochemical delay of 82 versus 43 days (P = 0.024), with biochemical delay defined as the length of time between PDT and a nonreversible increase in PSA to a value greater than or equal to baseline.
CONCLUSIONS
Results show PDT to induce large, transient increases in serum PSA levels. Patients who experienced high PDT dose showed greater short-term increase in PSA and a significantly more durable PSA response (biochemical delay). These data strongly promote the need for individualized delivery of PDT dose and assessment of treatment effect in PDT of prostate cancer. Information gained from such patient-specific measurements could facilitate the introduction of multiple PDT sessions in patients who would benefit.
Topics: Dose-Response Relationship, Drug; Humans; Light; Male; Metalloporphyrins; Models, Biological; Photochemotherapy; Photosensitizing Agents; Prostate-Specific Antigen; Prostatic Neoplasms; Radiometry; Recurrence; Time Factors; Treatment Outcome
PubMed: 18676760
DOI: 10.1158/1078-0432.CCR-08-0317 -
Arteriosclerosis, Thrombosis, and... May 2001Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The...
Motexafin lutetium is a photosensitizer that accumulates in atherosclerotic plaque and, after activation by far-red light, produces cytotoxic singlet oxygen. The combination of photosensitizer and illumination, known as photodynamic therapy (PDT), has been shown to reduce atheroma formation in animal models and is under clinical investigation. However, the effects of PDT with motexafin lutetium on isolated vascular cells are unknown. This study was designed to characterize the effects of PDT on vascular cell viability and to define the cell-death pathway for this agent. Fluorescence microscopy of RAW macrophages and human vascular smooth muscle cells revealed time-dependent uptake of motexafin lutetium. Illumination of motexafin lutetium-loaded cells with 732-nm light (2 J/cm(2)) impaired cellular viability and growth (IC(50) 5 to 20 micromol/L). Depletion of intracellular glutathione potentiated (P=0.035) and the addition of antioxidant N-acetylcysteine attenuated (P=0.002) cell death, suggesting that the intracellular redox state influences motexafin lutetium action. PDT was associated with the loss of mitochondrial membrane potential, mitochondrial release of cytochrome c, and caspase activation. PDT promoted phosphatidylserine externalization and induced apoptotic DNA fragmentation, with the number of apoptotic cells increasing from 7+/-2% to 34+/-3% of total cells. Reducing plaque cellularity by the induction of apoptosis may be one mechanism by which PDT reduces plaque burden, possibly modulates plaque vulnerability, and inhibits restenosis in vivo.
Topics: Animals; Apoptosis; Arteriosclerosis; Cell Division; Cell Line; Cell Survival; Cells, Cultured; Cytochrome c Group; Humans; Macrophages; Membrane Potentials; Metalloporphyrins; Mice; Mitochondria; Muscle, Smooth, Vascular; Oxidation-Reduction; Photochemotherapy; Photosensitizing Agents
PubMed: 11348871
DOI: 10.1161/01.atv.21.5.759 -
Journal of Environmental Pathology,... 2006Locally recurrent prostate cancer after treatment with radiation therapy is a clinical problem with few acceptable treatments. One potential treatment, photodynamic...
Locally recurrent prostate cancer after treatment with radiation therapy is a clinical problem with few acceptable treatments. One potential treatment, photodynamic therapy (PDT), is a modality that uses laser light, drug photosensitizer, and oxygen to kill tumor cells through direct cellular cytotoxicity and/or through destruction of tumor vasculature. A Phase I trial of interstitial PDT with the photosensitizer Motexafin lutetium was initiated in men with locally recurrent prostate cancer. In this ongoing trial, the primary objective is to determine the maximally tolerated dose of Motexafin lutetium-mediated PDT. Other objectives include evaluation of Motexafin lutetium uptake from prostate tissue using a spectrofluorometric assay and evaluation of optical properties in the human prostate. Fifteen men with biopsy-proven locally recurrent prostate cancer and no evidence of distant metastatic disease have been enrolled and 14 have been treated. Treatment plans were developed using transrectal ultrasound images. The PDT dose was escalated by increasing the Motexafin lutetium dose, increasing the 732 ran light dose, and decreasing the drug-light interval. Motexafin lutetium doses ranged from 0.5 to 2 mg/kg administered IV 24, 6, or 3 hr prior to 732 ran light delivery. The light dose, measured in real time with in situ spherical detectors was 25-100 J/cm2. Light was delivered via optical fibers inserted through a transperineal brachytherapy template in the operating room. Optical property measurements were made before and after light therapy. Prostate biopsies were obtained before and after light delivery for spectrofluorometric measurements of photosensitizer uptake. Fourteen patients have completed protocol treatment on eight dose levels without dose-limiting toxicity. Grade I genitourinary symptoms that are PDT related have been observed. One patient had Grade II urinary urgency that was urinary catheter related. No rectal or other gastrointestinal PDT-related tox-icities have been observed to date. Measurements of Motexafin lutetium demonstrated the presence of photosensitizer in prostate tissue from all patients. Optical property measurements demonstrated substantial heterogeneity in the optical properties of the human prostate gland which supports the use of individualized treatment planning for prostate PDT.
Topics: Adenocarcinoma; Aged; Humans; Male; Maximum Tolerated Dose; Metalloporphyrins; Middle Aged; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms
PubMed: 16566729
DOI: 10.1615/jenvironpatholtoxicoloncol.v25.i1-2.230 -
Journal of Chromatography. B,... Dec 2000We present new HPLC methods for the quantitation in human plasma of two investigative metallotexaphyrin agents, motexafin gadolinium (Gd-Tex) and motexafin lutetium...
We present new HPLC methods for the quantitation in human plasma of two investigative metallotexaphyrin agents, motexafin gadolinium (Gd-Tex) and motexafin lutetium (Lu-Tex). Each assay uses: the other texaphyrin analogue as an internal standard; protein precipitation with acetonitrile:methanol (50:50, v/v); an ODS reversed-phase column; an isocratic mobile phase of 100 mM ammonium acetate, pH 4.3:acetonitrile:methanol (59:21:20, v/v/v); and absorbance detection at 470 nm. The Gd-Tex assay has a lower limit of quantitation (LLOQ) of 0.01 microM and is linear between 0.01 and 30 microM. The Lu-Tex assay has an LLOQ of 0.1 microM and is linear between 0.1 and 30 microM. The assays are suited for in vivo preclinical studies and clinical trials because they require minimal amounts of plasma, are sensitive, and involve a 30-mm run time. These assays are important tools for evaluating the potential of Gd-Tex and Lu-Tex as a radiation enhancer and photosensitizer, respectively.
Topics: Chromatography, High Pressure Liquid; Humans; Metalloporphyrins; Photosensitizing Agents
PubMed: 11145051
DOI: 10.1016/s0378-4347(00)00390-x -
Photodiagnosis and Photodynamic Therapy Mar 2021This article is a review of approaches to treatment of low and high-grade prostate cancer including a discussion of active treatment vs. active surveillance for patients... (Review)
Review
This article is a review of approaches to treatment of low and high-grade prostate cancer including a discussion of active treatment vs. active surveillance for patients with low-grade prostate cancer. In particular, we will review PDT as an option for active treatment of low-grade prostate cancer considered in light of recent clinical trials. The mechanism and clinical methods of PDT application and the key points from clinical trials using PDT for prostate cancer with the photosensitizers m-tetrahydroxyphenyl chloride, protoporphyrin IX, motexafin lutetium, padoporfin, and padeliporfin between the years 2002 and 2017 are reviewed. Recently developed methodologies for photodynamic prostate cancer treatment that are in the experimental stage, photodynamic diagnosis, fluorescence guided resection, and PSMA-targeted PDT will also be discussed.
Topics: Humans; Male; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms
PubMed: 33352313
DOI: 10.1016/j.pdpdt.2020.102158 -
Clinical Cancer Research : An Official... Feb 2001Intraperitoneal photodynamic therapy (IP PDT) is an experimental cancer treatment in clinical development for the treatment of peritoneal carcinomatosis and... (Comparative Study)
Comparative Study
Intraperitoneal photodynamic therapy (IP PDT) is an experimental cancer treatment in clinical development for the treatment of peritoneal carcinomatosis and sarcomatosis. A canine study of motexafin lutetium (Lu-Tex)-mediated IP PDT was performed to evaluate normal tissue toxicities of this treatment in the presence and absence of a bowel resection and to assess the feasibility of measuring Lu-Tex fluorescence in abdominal tissues. Thirteen dogs were treated with Lu-Tex (0.2-2 mg/kg) i.v. 3 h before laparotomy and 730-nm light delivery (fluences, 0.5-2.0 J/cm2; average fluence rate <150 mW/cm2). Laparoscopy was performed 7-10 days after the procedure to assess acute toxicities. In situ fluorescence spectra were obtained from various abdominal tissues before and after light delivery using a fiber array probe with fixed-source detector distances. Lu-Tex-mediated IP PDT was well tolerated at the doses of drug and light studied. Bowel toxicity was not observed in animals treated with a bowel resection before PDT. Mild transient liver function test abnormalities without associated clinical sequelae were observed. No gross PDT-related abnormalities were observed at laparoscopy or necropsy; however, thickening in the glomerular capillary wall and the mesangium were noted microscopically in the kidneys of seven dogs. No renal function abnormalities were found. Analysis of the fluorescence spectra from intra-abdominal tissues suggests that measurements of Lu-Tex in situ are feasible and may provide a way of assessing photosensitizer concentration in vivo without the need for a biopsy. These results support the continued development of Lu-Tex as a candidate photosensitizer for IP PDT.
Topics: Abdomen; Animals; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Injections, Intraperitoneal; Kidney; Laparoscopy; Metalloporphyrins; Necrosis; Neoplasms; Photochemotherapy; Photosensitizing Agents; Treatment Outcome
PubMed: 11234893
DOI: No ID Found -
Oncotarget May 2017The search for new therapeutics for the treatment of prostate cancer is ongoing with a focus on the balance between the harms and benefits of treatment. New therapies... (Review)
Review
The search for new therapeutics for the treatment of prostate cancer is ongoing with a focus on the balance between the harms and benefits of treatment. New therapies are being constantly developed to offer treatments similar to radical therapies, with limited side effects. Photodynamic therapy (PDT) is a promising strategy in delivering focal treatment in primary as well as post radiotherapy prostate cancer. PDT involves activation of a photosensitizer (PS) by appropriate wavelength of light, generating transient levels of reactive oxygen species (ROS). Several photosensitizers have been developed with a focus on treating prostate cancer like mTHPC, motexafin lutetium, padoporfin and so on. This article will review newly developed photosensitizers under clinical trials for the treatment of prostate cancer, along with the potential advantages and disadvantages in delivering focal therapy.
Topics: Animals; Humans; Male; Photochemotherapy; Photosensitizing Agents; Prostatic Neoplasms; Reactive Oxygen Species; Treatment Outcome
PubMed: 28430624
DOI: 10.18632/oncotarget.15496 -
AAPS PharmSci 2003Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) methods were developed and validated for...
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and inductively coupled plasma-atomic emission spectroscopy (ICP-AES) methods were developed and validated for the evaluation of motexafin lutetium (MLu, lutetium texaphyrin, PCI-0123) pharmacokinetics in human plasma. The LC-MS/MS method was specific for MLu, whereas the ICP-AES method measured total elemental lutetium. Both methods were fast, simple, precise, and accurate. For the LC-MS/MS method, a closely related analogue (PCI-0353) was used as the internal standard (IS). MLu and the IS were extracted from plasma by protein precipitation and injected into an LC-MS/MS system configured with a C18 column and an electrospray interface. The lower limit of quantitation was 0.05 microg MLu mL(-1), with a signal-to-noise ratio of 15:1. The response was linear from 0.05 to 5.0 microg MLu mL(-1). For the ICP-AES method, indium was used as the IS. The sample was digested with nitric acid, diluted, filtered, and then injected into the ICP-AES system. Two standard curve ranges were validated to meet the expected range of sample concentrations: 0.5 to 50, and 0.1 to 10 microg Lu mL(-1). The LC-MS/MS and ICP-AES methods were validated to establish accuracy, precision, analyte stability, and assay robustness. Interday precision and accuracy of quality control samples were < or =6.3% coefficient of variation (CV) and within 2.2% relative error (RE) for the LC-MS/MS method, and < or =8.7% CV and within 4.9% RE for the ICP-AES method. Plasma samples from a subset of patients in a clinical study were analyzed using both methods. For a representative patient, over 90% of the elemental lutetium in plasma could be ascribed to intact MLu at early time points. This percentage decreased to 59% at 48 hours after dosing, suggesting that some degradation and/or metabolism of the drug may have occurred.
Topics: Chromatography, Liquid; Humans; Mass Spectrometry; Metalloporphyrins; Reproducibility of Results; Spectrophotometry, Atomic
PubMed: 14621958
DOI: 10.1208/ps050323