motexafin-gadolinium and Neoplasms

Redox regulation has been shown to be an important component of malignant cell survival. Tipping the cellular redox balance through pharmacologic regulation in favor of increasing intracellular reactive oxygen species (ROS) and/or depleting protective reducing metabolites (such as glutathione and nicotinamide adenine dinucleotide phosphate) may lead to oxidative stress and resultant induction of apoptosis for the treatment of cancer. We review the biology and importance of ROS with regard to malignant and normal cells. Moreover, we discuss pre-clinical and clinical data regarding novel therapeutic agents that modulate the cellular redox system including buthionine sulfoximine, ascorbic acid, arsenic trioxide, imexon, and motexafin gadolinium as single-agents and in combination. Continued research is needed to better understand the mechanisms and specific apoptotic pathways involved in ROS-induced cell death, as well as, to determine the most rationale and effective combination of redox-active agents.

Topics: Animals; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Buthionine Sulfoximine; Cell Death; Dose-Response Relationship, Drug; Glutathione; Hexanones; Humans; Metalloporphyrins; Models, Biological; Models, Chemical; Neoplasms; Oxidation-Reduction; Oxidative Stress; Oxides; Reactive Oxygen Species

Radiation therapy plays a critical role in the local and regional control of malignant tumors. Its efficacy, however, is limited by a number of factors, including toxicity, tumor hypoxia, and tumor genetics. Recent attempts to enhance the efficacy of radiation therapy have focused on biologic agents that modulate reduction/oxidation reactions within tumor cells.. We review five promising redox modulators that are in development. Tirapazamine and AQ4N are known as "hypoxic cell sensitizers" and are toxic in areas of low oxygen tension. RSR13 facilitates delivery of oxygen to tumor cells, thereby rendering them more sensitive to radiation. Motexafin gadolinium, with a porphyrin-like structure, selectively accumulates in tumor cells and thereby enhances radiation-induced DNA damage. HIF-1 inhibitors target a transcription factor that regulates hypoxia-related events and cell survival.. Our review of each agent included a thorough search of published preclinical and clinical data, including that presented in abstracts and posters at international meetings. Our objectives were not to identify a superior mechanism or drug, but rather to summarize the available safety and efficacy data.. Clearly, there is an unmet need for safer agents that augment the efficacy of radiation therapy. This review highlights five promising redox modulators that are in development. None has yet been approved by the Food and Drug Administration. These drugs were selected for discussion because they exemplify the current investigative landscape of radiosensitizers and are indicative of future directions in this area. These radiation sensitizers have the potential to succeed where others have failed, by locally increasing the radiosensitivity of tumor cells without enhancing that of surrounding normal tissues.

Topics: Aniline Compounds; Anthraquinones; Cell Hypoxia; Clinical Trials as Topic; DNA Damage; Drug Approval; Drug Therapy, Combination; Humans; Hypoxia-Inducible Factor 1; Maximum Tolerated Dose; Metalloporphyrins; Neoplasms; Oxidation-Reduction; Propionates; Radiation-Sensitizing Agents; Tirapazamine; Triazines

Motexafin gadolinium (MGd, Xcytrin) is an aromatic macrocycle that has a strong affinity for electrons, i.e., it is easily reduced. In the presence of oxygen, MGd accepts electrons from various cellular reducing metabolites and forms superoxide and other reactive oxygen species (ROS) by redox cycling. The reaction with NADPH is dramatically accelerated by various oxido-reductases including thioredoxin reductase. In vitro studies with various cancer cell lines have shown an increase in ROS and intracellular free zinc in cells treated with MGd. MGd increases cytotoxicity of ionizing radiation and various chemotherapy agents and may be directly cytotoxic to tumor cells under certain conditions. MGd selectively localizes in tumors, perhaps due to their metabolic perturbations. MGd treatment in murine models enhances tumor response to radiation and chemotherapy agents. In controlled, randomized clinical trials, combining MGd treatment with ionizing radiation improves time to neurologic progression in lung cancer patients with brain metastases. The molecular target for MGd appears to be thioredoxin reductase which, when inhibited, results in cellular redox stress, cytotoxicity and an increase in tumor responsiveness to a variety of treatments.

Topics: Antineoplastic Agents; Humans; Metalloporphyrins; Neoplasms; Oxidation-Reduction

Thioredoxin reductase (TRX) is a selenoprotein that reduces oxidized protein substrates in an NADPH-dependent process (cf. Fig. 1). The thioredoxins (TX) are a family of small redox active proteins that undergo reversible oxidation/reduction and help to maintain the redox state of cells. TX serves as a cofactor in many TRX-catalyzed reductions in a manner similar to glutathione (GSH) in thioltransferase reactions. For example, TX is a cofactor in protein disulfide reduction and DNA synthesis, but independently, it inhibits apoptosis, stimulates cell proliferation and angiogenesis, and increases transcription factor activity. The role of the TRX/TX system is limited by its reducing capacity as well as the additional supply of electrons in the form of NADPH provided by hexose monophosphate shunt (HMPS). TX is limited by the reduction capacity of its vicinal sulfhydryls and needs a source of electrons from the HMPS and TRX- coupled system to reduce disulfides. Oxidized TX is reduced by TRX and NADPH. Several lines of evidence suggest that the coupled HMPS/TRX/TX system represents an important target for cancer therapy. TX overexpression has been reported in several malignancies and may be associated with aggressive tumor growth and poor survival. In some cells, TX is an important factor in conferring resistance to chemotherapy and in stimulating production of hypoxia-inducible factor (HIF-1). Several inhibitors of the TRX/TX system have been evaluated in experimental cancer models: these include HMPS inhibitors, carbohydrate analogues, NADP synthesis blockers, vicinal thiol reactants, cisplatin, and TRX inhibitors. More recently, the targeted anti-cancer agent motexafin gadolinium has been identified. Motexafin gadolinium is a redox mediator that selectively localizes to cancer cells, and reacts with reducing metabolites and vicinal thiols to generate reactive oxygen species that ultimately block the TRX enzyme as well as the analogous glutaredoxin activity. In cell and animal models, motexafin gadolinium is directly cytotoxic to various tumor cells and enhances the activity of radiation therapy and chemotherapy. This drug is now in a broad range of clinical trials investigating its therapeutic potential when used as a single agent or in combination with either chemotherapy or radiation therapy. Promising clinical activity has been reported in a clinical trial with motexafin gadolinium and whole brain radiation therapy for treatment of brain metastases from

Topics: Antineoplastic Agents; Glycolysis; Humans; Metalloporphyrins; Neoplasms; Thioredoxin-Disulfide Reductase; Thioredoxins

Motexafin gadolinium [gadolinium (III) texaphyrin, gadolinium texaphyrin, Gd-Tex, GdT2B2, PCI 0120] is a radiosensitising agent developed for use in cancer therapy. It is cytotoxic in haematological malignancies by selectively localising in cancer cells that have high rates of metabolism. Motexafin gadolinium inhibits cellular respiration resulting in the production of reactive oxygen species and inducing apoptosis. It is being developed by Pharmacyclics in the US. Bulk motexafin gadolinium is supplied to Pharmacyclics by the US company, Celanese, through a manufacturing and supply agreement between the two companies. In June 2003, at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO-2003), the importance of having an agent for the treatment of brain metastases from lung cancer was highlighted. Results of a phase III study were presented that showed that motexafin gadolinium treatment was associated with a delay in time to neurological and neurocognitive progression in lung cancer patients. This was an important finding, as 46.6% of lung cancer patients already have brain metastases at the time of initial diagnosis, compared with only 2.7% of breast cancer patients. Brain metastases are also often the only site of metastatic disease in patients with lung cancer. In December 2002, Pharmacyclics began a phase III trial of motexafin gadolinium in patients with brain metastases (brain cancer in phase table) from lung cancer in the US, Europe, Canada and Australia. The trial is known as the Study of neurologic progression with Motexafin gadolinium And Radiation Therapy (SMART) and will compare whole-brain irradiation with whole-brain irradiation plus motexafin gadolinium in 550 patients. The primary efficacy endpoint is time to neurological progression and the secondary endpoints are survival and neurocognitive function. In January 2003, the US FDA completed its Special Protocol Assessment (SPA) of the SMART trial with a positive result and by June 2003, enrollment had begun. In addition, phase I trials are underway in children with intrinsic pontine glioma and adults with head and neck, lung and pancreatic cancers. A phase II trial is also being conducted in the US in patients with glioblastoma multiforme. Enrollment in this trial has been completed and preliminary results have been reported. Pharmacyclics has completed enrollment and follow-up of adults in its pivotal phase III trial of motexafin gadolinium as a radiation sensitiser

Topics: Animals; Drugs, Investigational; Humans; Metalloporphyrins; Neoplasms; Radiation-Sensitizing Agents

The generation of reactive oxygen species (ROS) can be exploited therapeutically in the treatment of cancer. One of the first drugs to be developed that generates ROS was procarbazine. It is oxidised readily in an oxic environment to its azo derivative, generating ROS. Forty years ago, Berneis reported a synergistic effect in DNA degradation when procarbazine was combined with radiation; this was confirmed in preclinical in vivo modes. Early uncontrolled clinical trials suggested an enhancement of the radiation effect with procarbazine, but two randomised trials failed to confirm this. The role of ROS in cancer treatments and in the development of resistance to chemotherapy is now better understood. The possibility of exploiting ROS as a cancer treatment is re-emerging as a promising therapeutic option with the development of agents such as buthionine sulfoximine and motexafin gadolinium.

Topics: Antineoplastic Agents; Buthionine Sulfoximine; Combined Modality Therapy; DNA; Humans; Metalloporphyrins; Neoplasms; Oxidation-Reduction; Procarbazine; Reactive Oxygen Species

The texaphyrins are quintessential metal-coordinating expanded porphyrins. They constitute a new series of synthetic porphyrin analogues that show promise as drugs for use in a range of medical therapies. Currently, two different water-solubilized lanthanide(III) texaphyrin complexes, namely the gadolinium(III) and lutetium(III) derivatives 1 and 2 (Gd-Tex and Lu-Tex, respectively), are being tested clinically. The first of these, XCYTRIN, is in a pivotal Phase III clinical trial as a potential enhancer of radiation therapy for patients with metastatic cancers to the brain receiving whole brain radiation therapy. The second, in various formulations, is being tested as a photosensitizer for use in: (i) the photodynamic treatment of recurrent breast cancer (LUTRIN; Phase II clinical trials complete), (ii) photoangioplastic reduction of atherosclerosis involving peripheral arteries (ANTRIN; now in Phase II testing), and (iii) light-based treatment of age-related macular degeneration (OPTRIN; currently in Phase I clinical trials), a vision-threatening disease of the retina. Taken in concert, these two metallotexaphyrins provide a powerful new class of experimental drugs whose diverse potential utility is abetted by a combination of well-optimized physical features, favorable tissue biolocalization characteristics, and novel mechanisms of action. Interestingly, these mechanisms may alter conventional wisdom regarding mechanisms of radiation therapy and the pathophysiology of atherosclerosis.

Topics: Arteriosclerosis; Clinical Trials as Topic; Humans; Macular Degeneration; Metalloporphyrins; Neoplasms; Photochemotherapy; Photosensitizing Agents; Radiation Tolerance

That hypoxic tissues are more resistant to the effects of radiation than well-oxygenated tissues has been known for many decades, and repeated in vitro demonstrations have confirmed that to achieve the same degree of cytotoxicity, hypoxic cells require about three times the radiation dose that well-oxygenated cells need. Hypoxic cell sensitizers enhance the tissue response to standard radiation, generally by mimicking the effects of oxygen, which induces the formation and stabilization of toxic DNA radicals. Although many hypoxic cell sensitizers like the nitroimidazoles have been evaluated in combination with radiation, these agents have had no or only minimal therapeutic impact due to either their limited potency or their toxicity at biologically relevant concentrations. This article reviews several new modalities that either increase oxygen delivery or sensitize hypoxic tissues. These modalities, all currently in early clinical evaluations, include: (1) tirapazamine, a bioreductive agent; (2) gadolinium texaphyrin, a hypoxic cell sensitizer with biolocalization properties using magnetic resonance imaging; (3) RSR13, an allosteric modifier of hemoglobin; and (4) bovine hemoglobin modified by the attachment of polyethylene glycol polymers.

Topics: Animals; Antineoplastic Agents; Cell Hypoxia; Clinical Trials as Topic; Combined Modality Therapy; DNA Damage; Hemoglobins; Humans; Metalloporphyrins; Neoplasms; Radiation-Sensitizing Agents; Tirapazamine; Triazines

To assess the safety, maximum-tolerated dose (MTD), and dose-limiting toxicities (DLT), of motexafin gadolinium (MGd), given in combination with doxorubicin, in patients with advanced solid tumors.. The combination of MGd and doxorubicin was administered every 28 days (cycle 1) and then every 21 days (subsequent cycles). The dose of MGd, given daily for 3 days, was escalated from 1.0 mg/kg/d to 3.3 mg/kg/d, while the dose of doxorubicin was held at 30 mg/m².. Fifteen patients received 37 cycles of treatment, for a median of 2 cycles per patient (range 0-6 cycles). Three patients (20%) completed 6 cycles of therapy. The MTD was identified as MGd, 2 mg/kg/day and doxorubicin, 30 mg/m². Dose limiting toxicities included grade 3 hypertension, pneumonia, bacteremia, and elevated GGT. Serious adverse events also included pulmonary embolism and urinary tract infection requiring hospitalization. There was no exacerbation of cardiac toxicity. No patients attained a response to treatment. Six patients (54%) had stable disease. The median time to disease progression, or to last assessment, was 49 days (range 8-195 days).. The combination of MGd and doxorubicin was fairly well tolerated. However, due to emerging preclinical data suggesting that MGd inhibits ribonucleotide reductase, further development of the combination of MGd plus doxorubicin is not recommended.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Demography; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Male; Metalloporphyrins; Middle Aged; Neoplasms; Treatment Outcome

To determine the safety, tolerability, and report on secondary efficacy endpoints of motexafin gadolinium (MGd) in combination with whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) for patients with ≤ 6 brain metastases. We conducted an international study of WBRT (37.5 Gy in 15 fractions) and SRS (15-21 Gy) with the addition of MGd (5 mg/kg preceding each fraction beginning week 2). The primary endpoint was to evaluate the rate of irreversible grade 3 or any grade ≥ 4 neurotoxicity and establish feasibility in preparation for a phase III trial. Sixty-five patients were enrolled from 14 institutions, of which 45 (69%) received SRS with MGd as intended and were available for evaluation. Grade ≥ 3 neurotoxicity attributable to radiation therapy within 3 months of SRS was seen in 2 patients (4.4%), including generalized weakness and radionecrosis requiring surgical management. Immediately following the course of MGd plus WBRT, new brain metastases were detected in 11 patients (24.4%) at the time of the SRS treatment planning MRI. The actuarial incidence of neurologic progression at 6 months and 1 year was 17 and 20%, respectively. The median investigator-determined neurologic progression free survival and overall survival times were 8 (95% CI: 5-14) and 9 months (95% CI: 6-not reached), respectively. We observed a low rate of neurotoxicity, demonstrating that the addition of MGd does not increase the incidence or severity of neurologic complications from WBRT with SRS boost.

Topics: Adult; Aged; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Feasibility Studies; Female; Follow-Up Studies; Humans; International Agencies; Male; Metalloporphyrins; Middle Aged; Neoplasm Recurrence, Local; Neoplasms; Radiosurgery; Survival Rate; Treatment Outcome

Gadolinium (III) texaphyrin (Gd-Tex) (NSC 695238) is a potential radiation sensitizer that selectively localizes in tumors and is detectable by magnetic resonance imaging (MRI). In this single-dose phase I trial, reversible renal injury was the dose-limiting toxicity. This report details that renal injury. A single intravenous dose of Gd-Tex was followed 2 hours later by radiation therapy. The Gd-Tex dose was escalated in 13 patient cohorts. Doses ranged from 0.6 to 29.6 mg/kg. The maximum tolerated dosage (MTD) was 22.3 mg/kg. Three patients had grade II and one had grade III acute nonoliguric renal failure at the 22.3 and 29.6 mg/kg dose levels. The injury was always transient, and responded to fluid restriction and renal diet. In all patients, transient green discoloration including urine developed at doses > or =7.1 mg/kg. MRI studies demonstrated image enhancement in the liver, kidneys, and in primary and metastatic tumors in all patients receiving >5.4 mg/kg. It is important that the liver and kidneys be excluded from the radiation volume. Gd-Tex was well tolerated at doses below the MTD. It is important that the liver and kidneys be excluded from the radiation volume. We recommend that 16.7 mg/kg be used as the maximum single dose to obviate even low grade renal toxicity.

Topics: Adult; Biomarkers; Dose-Response Relationship, Drug; Female; Gadolinium; Humans; Kidney Diseases; Male; Metalloporphyrins; Middle Aged; Neoplasms; Palliative Care; Radiation-Sensitizing Agents

Gadolinium Texaphyrin (Gd-Tex) is a radiation sensitizer with a novel mechanism of action that sensitizes both oxic and hypoxic cells, localizes selectively in tumors, and is detectable by magnetic resonance imaging (MRI). This Phase I single-dose trial of Gd-Tex administered concurrently with radiation therapy was carried out to determine the maximally tolerated dose (MTD), dose-limiting toxicities, pharmacokinetics, and biolocalization of Gd-Tex as determined by MRI. Adults with incurable cancers of any histology requiring radiation therapy were eligible. A single i.v. dose of Gd-Tex was followed at least 2 h later by radiation therapy. The Gd-Tex dose was escalated in cohorts of 3 to 5 patients. Thirty-eight patients (median age, 58 years; range, 35-77 years) with incurable cancers of the lung (26), cervix (3), or other solid tumors (9) received a total of 41 single administrations of Gd-Tex. The Gd-Tex dose was escalated from 0.6 to 29.6 mg/kg. Irradiated sites included the thorax, brain, pelvis, bone, soft tissue, and sites of nodal metastases. The MTD was 22.3 mg/kg, determined by reversible acute tubular necrosis as the dose-limiting toxicities. Gd-Tex selectively accumulated in primary and metastatic tumors as demonstrated by MRI. No increase in radiation toxicity to normal tissues was seen. The median half-life of Gd-Tex after single-dose administration is 7.4 h. This study demonstrates that Gd-Tex is well tolerated in doses below the MTD, and that there is selective biolocalization in tumors. The maximum recommended dose for single administrations is 16.7 mg/kg.

Topics: Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Digestive System; Dose-Response Relationship, Drug; Drug Eruptions; Female; Hematopoiesis; Humans; Kidney; Liver; Magnetic Resonance Imaging; Male; Metalloporphyrins; Middle Aged; Neoplasms; Radiation-Sensitizing Agents; Tissue Distribution

Topics: Acquired Immunodeficiency Syndrome; Female; Humans; Injections, Intravenous; Lighting; Lutetium; Male; Metalloporphyrins; Neoplasms; Photochemotherapy; Photosensitizing Agents; Sarcoma, Kaposi

Topics: Gadolinium; Humans; Magnetic Resonance Imaging; Myoglobin; Neoplasms; Oxygen; Radiation-Sensitizing Agents

MRI is often used in tumor localization for radiotherapy treatment planning, with gadolinium (Gd)-containing materials often introduced as a contrast agent. Motexafin gadolinium is a novel radiosensitizer currently being studied in clinical trials. The nanoparticle technologies can target tumors with high concentration of high-Z materials. This Monte Carlo study is the first detailed quantitative investigation of high-Z material Gd-induced dose enhancement in megavoltage external beam photon therapy. BEAMnrc, a radiotherapy Monte Carlo simulation package, was used to calculate dose enhancement as a function of Gd concentration. Published phase space files for the TrueBeam flattening filter free (FFF) and conventional flattened 6MV photon beams were used. High dose rate (HDR) brachytherapy with Ir-192 source was also investigated as a reference. The energy spectra difference caused a dose enhancement difference between the two beams. Since the Ir-192 photons have lower energy yet, the photoelectric effect in the presence of Gd leads to even higher dose enhancement in HDR. At depth of 1.8 cm, the percent mean dose enhancement for the FFF beam was 0.38±0.12, 1.39±0.21, 2.51±0.34, 3.59±0.26, and 4.59±0.34 for Gd concentrations of 1, 5, 10, 15, and 20 mg/mL, respectively. The corresponding values for the flattened beam were 0.09±0.14, 0.50±0.28, 1.19±0.29, 1.68±0.39, and 2.34±0.24. For Ir-192 with direct contact, the enhanced were 0.50±0.14, 2.79±0.17, 5.49±0.12, 8.19±0.14, and 10.80±0.13. Gd-containing materials used in MRI as contrast agents can also potentially serve as radiosensitizers in radiotherapy. This study demonstrates that Gd can be used to enhance radiation dose in target volumes not only in HDR brachytherapy, but also in 6 MV FFF external beam radiotherapy, but higher than the currently used clinical concentration (>5 mg/mL) would be needed.

Topics: Brachytherapy; Contrast Media; Gadolinium; Humans; Metalloporphyrins; Monte Carlo Method; Neoplasms; Radiation-Sensitizing Agents; Radiotherapy Dosage

Highly efficient apoptotic hyperthermia is achieved using a double-effector nanoparticle that can generate reactive oxygen species (ROS) and heat. ROS render cancer cells more susceptible to subsequent heat treatment, which remarkably increases the degree of apoptotic cell death. Xenograft tumors (100 mm(3)) in mice are completely eliminated within 8 days after a single mild magnetic hyperthermia treatment at 43 °C for 30 min.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Humans; Hyperthermia, Induced; Magnetic Fields; Metal Nanoparticles; Metalloporphyrins; Mice; Neoplasms; Reactive Oxygen Species; Temperature; Transplantation, Heterologous

To gain a better understanding of the mechanism of action of the metal cation-containing chemotherapeutic drug motexafin gadolinium (MGd), gene expression profiling analyses were conducted on plateau phase human lung cancer (A549) cell cultures treated with MGd. Drug treatment elicited a highly specific response that manifested in elevated levels of metallothionein isoform and zinc transporter 1 (ZnT1) transcripts. A549 cultures incubated with MGd in the presence of exogenous zinc acetate displayed synergistic increases in the levels of intracellular free zinc, metallothionein transcripts, inhibition of thioredoxin reductase activity, and cell death. Similar effects were observed in PC3 prostate cancer and Ramos B-cell lymphoma cell lines. Intracellular free zinc levels increased in response to treatment with MGd in the absence of exogenous zinc, indicating that MGd can mobilize bound intracellular zinc. These findings lead us to suggest that an important component of the anticancer activity of MGd is related to its ability to disrupt zinc metabolism and alter cellular availability of zinc. This class of compounds may provide insight into the development of novel cancer drugs targeting control of intracellular free zinc and the roles that zinc and other metal cations play in biochemical pathways relevant to cancer.

Topics: Acetates; Antineoplastic Agents; Cadmium; Cell Line, Tumor; Cell Proliferation; Drug Synergism; Gene Expression; Gene Expression Profiling; Humans; Lung Neoplasms; Lymphoma, B-Cell; Male; Metalloporphyrins; Neoplasms; Oxidation-Reduction; Prostatic Neoplasms; Thioctic Acid; Zinc; Zinc Acetate

Topics: Adenine Nucleotides; Antineoplastic Agents; Arabinonucleosides; Cancer Vaccines; Clofarabine; Cytokines; Epidermal Growth Factor; Glucocorticoids; Humans; Interleukin-2; Metalloporphyrins; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sirolimus

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