Efficacy of Systemic Radionuclide Therapy with p-¹³¹I-Iodo-l-Phenylalanine Combined with External Beam Photon Irradiation in Treating Malignant Gliomas

Abstract

p-131 I-iodo-L-phenylalanine ( 131 I-IPA) is a tumor-specific amino acid derivative that demonstrated antiproliferative and tumoricidal effects on experimental gliomas. This study tested the efficacy of 131 I-IPA combined with external beam photon radiotherapy as a new therapeutic approach against gliomas. Methods: Glioma cells derived from the rat F98 glioma or human Tx3868 or A1207 glioblastoma cell lines were stereotactically inoculated into the brains of Fischer 344 rats or RNU rats. Tumor formation was verified radiologically. On day 8, groups of glioma-bearing rats of each tumor model underwent whole-brain radiotherapy with 8 Gy, an intravenous administration of 131 I-IPA (30 MBq), or combined treatment, aiming for a total of 12 rats per group. Another 12 animals were treated with physiologic saline and served as control. Results: Control rats had a combined median survival (6SD) of 21 6 6 d. All revealed metabolically and histologically large tumor masses. Efficacy of radiotherapy alone or a monotherapy with 30 MBq of 131 I-IPA was statistically insignificant on the syngeneic Fischer-F98 model (P $ 0.45 and P 5 0.10, respectively). In contrast, a subset of long-term survivors (.120 d) was observed in RNU rats bearing Tx3868 and A1207 glioblastoma xenografts (18%225% and 35%245% for radiotherapy and 131 I-IPA, respectively). Combined 131 I-IPA and radiotherapy treatment significantly prolonged median survival for the syngeneic Fischer-F98 glioma model (P , 0.01) and human glioblastoma-bearing RNU rats alike (P , 0.05). On day 120 after monotherapy with 131 I-IPA, 45% of the RNU rats were still alive, but after 8 Gy of photon radiotherapy only 18%225% of the RNU and none of the Fischer rats survived. In comparison, 55%275% survival rates were registered after combined treatment on day 120 for all animal models. Conclusion: These data convincingly demonstrated that systemic radionuclide therapy with 131 I-IPA combined with external photon radiotherapy is a safe and highly effective treatment for experimental gliomas, which may merit a clinical trial to ascertain its potential in patients with gliomas. Because only a low 131 I-IPA activity and low radiotherapy doses were applied, further optimizations including higher radiation doses and conventional fractionated radiotherapy are warranted.

Systemic Endoradiotherapy with Carrier-Added 4-[131I]Iodo-L-Phenylalanine: Clinical Proof-of-Principle in Refractory Glioma

“…In the patients reported here, neither acute nor delayed radiotoxicity to bone marrow, kidney, brain or other systems were observed to date, in spite of systematic screening. This result confirms our previous findings based on animal studies [18,19]. Indeed, internal dosimetry, performed according to MIRD recommendations [21] and obtained in three treatment cycles, demonstrates that absorbed doses to radiation-critical organs, such as red marrow, kidney, liver and gonads, are comparable with those reported for established endoradiotherapy agents, like iodine-131 for the treatment of thyroid malignancies or 131 I-MIBG for pheochromoticytoma or neuroblastoma [10,26].…”

“…Due to their structural and pharmacological identity, carrier and 131 I-IPA are taken up by the tumour cells simultaneously in proportion to their molecular occurrence, defined by the specific activity. As non-radioactive IPA possesses both an intrinsic cytostatic and an independent radiosensitiser effect [19], c.a. 131 I-IPA is likely to exert a multimodal antineoplastic activity at the cellular level, which differentiates it from other endoradiotherapy agents or chemotherapeutics used in glioma therapy.…”

“…131 I-IPA was prepared by isotopic radio-iodination in analogy to the method described previously [19]. Briefly, a mixture consisting of sodium [ 131 I]iodide (2)(3)(4)(5) in 100-500 μl 0.05 N NaOH (GE Healthcare, Germany) and 10 μl aqueous Na 2 S 2 O 5 (4.0 mg Na 2 S 2 O 5 /ml) was evaporated to dryness by passing a stream of nitrogen through a 5-m conical Reactivial (Alltech Associates, Deerfield, IL, USA) at 90°C, followed by addition of 500 μl of a solution of 4-iodo-L-phenylalanine (2.5 mg/ml of 0.1 M H 3 PO 4 ), 15 μl 30% HCl (suprapur; Merck, Germany), 200 μl L-ascorbic acid (10 mg/ml water), and 10 μl aqueous Cu(II) sulphate (0.10 mol/l).…”

“…4-[ 123 I]Iodo-L-phenylalanine ( 123 I-IPA) is a new SPECT tracer, recently described in a validation study which was conducted in 35 patients with histologically confirmed glioma (WHO grade I-IV, primary tumours as well as recurrences) and demonstrated retention in glioma tissue for up to 24 h, high metabolic stability, and uptake by >85% of gliomas WHO grade I-IV [17] which previously had not been reported for any of the iodinated amino acid derivatives. These characteristics prompted the evaluation of the 131 I-labelled analogue 131 I-IPA as a therapeutic agent for endoradiotherapy of glioma [18,19].…”

Improved synthesis of [18F]FS-PTAD as a new tyrosine-specific prosthetic group for radiofluorination of biomolecules

“…The glioma cells were cultured as described previously (Samnick et al, 2009;Israel et al, 2011). In details: T3868 and F98 cells were grown in Dulbecco's Modified Eagle's Medium (DMEM) supplemented with glucose (4.5 g/L), 10% fetal bovine serum (FBS), L-glutamine (584 mg/L) and 1% penicillin (100 IU/mL)/streptomycin (100 μg/mL) (Life Technologies GmbH, Darmstadt, Germany) and A1207 cells in Royal Park Memorial Institute (RPMI)-1640 medium supplemented with glucose (4.5 g/L), 10% fetal bovine serum (FBS), L-glutamine (300 mg/L) and 1% penicillin (100 IU/mL)/streptomycin (100 μg/mL) (Life Technologies GmbH, Darmstadt, Germany).…”