motexafin-lutetium and Adenocarcinoma

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

Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed extensive studies that demonstrate the feasibility of interstitial PDT for prostate cancer. Our preclinical and clinical experience is herein detailed.. We have treated 16 canines in preclinical studies, and 16 human subjects in a Phase I study, using motexafin lutetium-mediated PDT for recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and oxygen distribution for these patients were performed.. We demonstrate the safe and comprehensive treatment of the prostate using PDT. However, there is significant variability in the dose distribution and the subsequent tissue necrosis throughout the prostate.. PDT is an attractive option for the treatment of prostate adenocarcinoma. However, the observed variation in PDT dose distribution translates into uncertain therapeutic reproducibility. Our future focus will be on the development of an integrated system that is able to both detect and compensate for dose variations in real-time, in order to deliver a consistent overall PDT dose distribution.

Topics: Adenocarcinoma; Aged; Animals; Dogs; Dose-Response Relationship, Drug; Hemoglobins; Humans; Male; Metalloporphyrins; Middle Aged; Necrosis; Neoplasm Recurrence, Local; Oxygen; Photochemotherapy; Photosensitizing Agents; Prostate; Prostatic Neoplasms; Regional Blood Flow

The use of near-infrared (NIR)-excited Fourier-transform (FT) Raman spectroscopy as a technique for evaluating the extent of photosensitizer localization in tumor (human pancreatic adenocarcinomas)-bearing mice has been tested using lutetium(III) texaphyrin analogue Lu-T2B2Tex. The complex was injected subcutaneously in the form of three injections given during the course of 3 days. The kinetics of biodistribution were then followed over a time scale of 1-6 days. The NIR-FT-Raman spectra of tissue samples obtained from the xenographic tumor, muscle, heart, brain, liver, spleen, kidney and blood were recorded and used to identify the presence of Lu-T2B2Tex in these tissues. Five Raman sensitizer markers were used to estimate the relative content of Lu-T2B2Tex in tumor at various postinjection times. UV-Visible (Vis) absorption spectroscopic detection of this sensitizer in tissue extracts was applied as a conventional method. Both spectroscopic methods were in good agreement with each other and confirm that Lu-T2B2Tex localizes well in tumor tissue. Maximal drug content was observed 3 days after the final injection. This time delay seems to be optimal for tumor irradiation in photodynamic therapy.

Topics: Adenocarcinoma; Animals; Cell Line, Tumor; Female; Humans; Metalloporphyrins; Mice; Mice, Inbred Strains; Mice, Nude; Models, Animal; Molecular Structure; Neoplasm Transplantation; Nitrates; Pancreatic Neoplasms; Photosensitizing Agents; Spectrophotometry, Ultraviolet; Spectroscopy, Fourier Transform Infrared; Spectroscopy, Near-Infrared; Spectrum Analysis, Raman; Tissue Distribution

New photosensitizers proposed for photodynamic therapy (PDT) treatment of tumors need to be evaluated in animal models to determine the parameters needed for treatment. They also need to be compared with existing photosensitizers for efficacy. We examined the PDT response to lutetium-texaphyrin (PCI-0123) in a mouse mammary adenocarcinoma model and compared it with the PDT response seen when using Photofrin.. DBA/2 mice with SMT-F tumors were used to explore PCI-0123 toxicity, laser light dose, and drug dose effects on PDT response and to determine the most effective time for light application. The PDT response of PCI-0123-treated tumors was compared with that of Photofrin-treated tumors.. Treatment of tumors with 150 J/cm2 of 740 nm laser light 5-6 hr after PCI-0123 administration (40 mg/kg) resulted in a 100% response rate and a 55% cure rate. Tumors treated with 150 J/cm2 of 630 nm laser light 24 hr after Photofrin administration (10 mg/kg) resulted in a 67% response rate and a 16% cure rate.. PCI-0123 was found to be a more effective photosensitizer than Photofrin.

Topics: Adenocarcinoma; Animals; Dihematoporphyrin Ether; Female; Laser Therapy; Mammary Neoplasms, Animal; Metalloporphyrins; Mice; Mice, Inbred DBA; Photochemotherapy; Photosensitizing Agents; Tumor Cells, Cultured