motexafin-gadolinium and Glioma

To evaluate the effects on 1-year event-free survival (EFS) and overall survival (OS) of combining motexafin and gadolinium (MGd), a potent radiosensitizer, with daily fractionated radiation therapy in children with newly diagnosed intrinsic pontine gliomas.. Patients with newly diagnosed intrinsic pontine glioma were treated with MGd daily for 5 consecutive days each week, for a total of 30 doses. Patients received a 5- to 10-min intravenous bolus of MGd, 4.4 mg/kg/day, given 2 to 5 h prior to standard dose irradiation. Radiation therapy was administered at a daily dose of 1.8 Gy for 30 treatments over 6 weeks. The total dose was 54 Gy.. Sixty eligible children received MGd daily, concurrent with 6 weeks of radiation therapy. The estimated 1-year EFS was 18%±5%, and the estimated 1-year OS was 53%±6.5%. The most common grade 3 to 4 toxicities were lymphopenia, transient elevation of liver transaminases, and hypertension.. Compared to historical controls, the addition of MGd to a standard 6-week course of radiation did not improve the survival of pediatric patients with newly diagnosed intrinsic pontine gliomas.

Topics: Adolescent; Brain Stem Neoplasms; Child; Child, Preschool; Disease-Free Survival; Dose Fractionation, Radiation; Drug Administration Schedule; Female; Glioma; Humans; Hypertension; Infant; Infusions, Intravenous; Liver; Lymphopenia; Male; Metalloporphyrins; Pons; Radiation-Sensitizing Agents

The purpose of this study was to determine the dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, and intratumor and brain distribution of motexafin gadolinium (MGd) with involved field radiation therapy in children with newly diagnosed intrinsic pontine gliomas. MGd was administered as a 5-min intravenous bolus 2-5 h prior to standard radiation. The starting dose was 1.7 mg/kg. After first establishing that 5 doses/week for 6 weeks was tolerable, the dose of MGd was escalated until dose-limiting toxicity was reached. Radiation therapy was administered to 54 Gy in 30 once-daily fractions. Forty-four children received MGd at doses of 1.7 to 9.2 mg/kg daily prior to radiation therapy for 6 weeks. The maximum tolerated dose was 4.4 mg/kg. The primary dose-limiting toxicities were grade 3 and 4 hypertension and elevations in serum transaminases. Median elimination half-life and clearance values were 6.6 h and 25.4 ml/kg/h, respectively. The estimated median survival was 313 days (95% confidence interval, 248-389 days). The maximum tolerated dose of MGd and the recommended phase II dose was 4.4 mg/kg when administered as a daily intravenous bolus in conjunction with 6 weeks of involved field radiation therapy for pediatric intrinsic pontine gliomas.

Topics: Adolescent; Adult; Area Under Curve; Brain Stem Neoplasms; Child; Child, Preschool; Combined Modality Therapy; Female; Glioma; Half-Life; Humans; Magnetic Resonance Imaging; Male; Maximum Tolerated Dose; Metalloporphyrins; Pons; Radiation-Sensitizing Agents; Radiotherapy

To investigate the possibility of using motexafin gadolinium (MGd)-enhanced molecular magnetic resonance (MR) imaging and optical imaging to identify the true margins of gliomas.. The animal protocol was approved by the institutional animal care and use committee. Thirty-six Sprague-Dawley rats with gliomas were randomized into six groups of six rats. Five groups were euthanized 15, 30, 60, 120, and 240 minutes after intravenous administration of 6 mg/kg of MGd, while one group received only saline solution as a control group. After craniotomy, optical imaging and T1-weighted MR imaging were performed to identify the tumor margins. One-way analysis of variance was used to compare optical photon intensity and MR imaging signal-to-noise ratios. Histologic analysis was performed to confirm the intracellular uptake of MGd by tumor cells and to correlate the tumor margins delineated on both optical and MR images.. Both optical imaging and T1-weighted MR imaging showed tumor margins. The highest optical photon intensity (2.6 × 10(8) photons per second per mm(2) ± 2.3 × 10(7); analysis of variance, P < .001) and MR signal-to-noise ratio (77.61 ± 2.52; analysis of variance, P = .006) were reached at 15-30 minutes after administration of MGd, with continued tumor visibility at 2-4 hours. Examination with confocal microscopy allowed confirmation that the fluorescence of optical images and MR imaging T1 enhancement exclusively originated from MGd that accumulated in the cytoplasm of tumor cells.. MGd-enhanced optical and MR imaging can allow determination of glioma tumor margins at the optimal time of 15-120 minutes after administration of MGd. Clinical application of these results may allow complete removal of gliomas in a hybrid surgical setting in which intraoperative optical and MR imaging are available.

Topics: Animals; Brain Neoplasms; Contrast Media; Craniotomy; Disease Models, Animal; Glioma; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Metalloporphyrins; Microscopy, Confocal; Molecular Imaging; Random Allocation; Rats; Rats, Sprague-Dawley; Signal-To-Noise Ratio; Tumor Cells, Cultured

Photodynamic therapy (PDT) has been investigated as a postoperative treatment in patients with high grade gliomas. The purpose of this in vitro investigation was to determine whether motexafin gadolinium (MGd), a known radiation sensitizer, could potentiate the effects of 5-aminolevulinic acid (ALA)-PDT. Human glioma (ACBT) spheroids (250 microm diameter) were incubated in 5-aminolevulinic acid (ALA) with and without MGd and irradiated with 635 nm light for a total light fluence of 6, 12, or 18 J cm(-2) delivered at a fluence rate of 5 mW cm(-2). Spheroid growth was monitored for a period of 4 weeks following each treatment. In another set of experiments, 400-500 microm diameter ACBT spheroids were implanted into a gel collagen matrix and subjected to ALA-PDT (fluence: 3 or 6 J cm(-2)), MGd, or a combination of ALA-PDT and MGd. The migration distance of surviving glioma cells in each treatment group was recorded over a 5-day period. The results showed that MGd interacted with PDT in a synergistic manner resulting in greater cytotoxicity than that achievable with either treatment modality alone. The degree of synergism was shown to increase with increasing light fluence. At the highest light fluence investigated (18 J cm(-2)), the percentage of spheroids demonstrating growth 4 weeks following exposure to MGd, ALA-PDT, or MGd + ALA-PDT was 100%, 75%, and 15%, respectively. The results of cell migration studies revealed that the combination of PDT and MGd produced a significant inhibitory effect on glioma cell migration: the addition of MGd resulted in an approximately three times reduction in migration distance compared with PDT alone. Overall, the results suggest that MGd can potentiate both the cytotoxic and migration inhibitory effects of ALA-PDT and hence, this combined therapeutic approach has the potential to extend treatment volumes in patients with malignant gliomas.

Topics: Aminolevulinic Acid; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Dose-Response Relationship, Radiation; Drug Synergism; Ethidium; Glioma; Humans; Metalloporphyrins; Neoplasm Invasiveness; Photochemotherapy; Spheroids, Cellular; Time Factors

The characteristics of an ideal contrast agent for use in the intraoperative MRI would be tumor-specificity and intracellular localization, combined with extended tumor enhancement, but with rapid elimination from the blood. The radiation sensitizing properties of Motexafin gadolinium (MGd) have been investigated in a number of clinical trials involving patients with brain metastases. These studies clearly show that MGd is detectable in magnetic resonance images many days following administration. The aim of this experimental study was to test whether Motexafin gadolinium (MGd) could serve as an efficient intraoperative contrast agent avoiding problems that arise with surgically induced intracranial enhancement.. F98 orthotopic brain tumors or surgical lesions were induced in Fisher rats. T1-weighted MRI studies were performed with either a single or multiple daily doses of MGd. The last contrast dose was administered either 7 or 24 hours prior to scanning in both tumor-bearing or surgically-treated animals. All scans were T1-weighted nce (TR=495 ms; TE=1 ms.) with a slice thickness of 1.0 mm. Three tubes containing 2.3, 0.23 and 0.023 mg/mL of MGd (in physiological saline) respectively, were used as standards to calibrate the scans.. Animals receiving either 30 or 60 mg/kg MGd i.v. developed clinical signs of impaired motor activity, and increasing lethargy and were euthanized 48 hours after MGd administration due to their poor and deteriorating condition. MGd given i.p. was tolerated up to a dose of 140 mg/kg. Despite multiple dosages and several administration modes (i.p., i.v.) no significant enhancement was observed if the scans were performed 7 or 24 hours following the last MGd dose. Clear enhancement was seen though when the scans were performed 30 min following MGd administration, indicating that the agent was being taken up by the tumor. Scans of necrotic lesions though were positive though 7 hours following MGd injection. MGd scans had no significant enhancement following surgically-induced lesions while scans with conventional contrast agents showed both meningeal and intraparenchymal enhancement.. This study suggests that MGd is not sequestered in viable tumor for the necessary time interval required to allow delayed imaging in this model. The agent does seem to remain in necrotic tissue for longer time intervals. MGd therefore would not be suitable as a contrast agent in intraoperative MRI for the detection of remaining tumor tissue during surgery.

Topics: Animals; Blood-Brain Barrier; Brain Neoplasms; Cell Line, Tumor; Cerebrovascular Circulation; Contrast Media; Disease Models, Animal; Encephalitis; Female; Glioma; Injections, Intraperitoneal; Injections, Intravenous; Magnetic Resonance Imaging; Male; Metabolic Clearance Rate; Metalloporphyrins; Monitoring, Intraoperative; Photic Stimulation; Photochemotherapy; Predictive Value of Tests; Rats; Rats, Inbred F344