No abstract

An alpha-emitting immunoconjugate (AIC) against malignant melanoma was prepared from the radioisotope bismuth-213 and a melanoma monoclonal antibody, and was used to control the growth of subcutaneous melanoma in a nude mouse model. Activity tolerances were found to be 8 mCi/kg for intraperitoneal injection of the conjugate, and 10 mCi/kg for intralesional injections. Local targeted alpha therapy (TAT) via intralesional injections of activities in the range 12.5-200 microCi shows a very high level of inhibition of tumorigenesis and regression of tumours. Results show that isolated cancer cells and preangiogenic cell clusters can be eliminated by local TAT, and that intralesional injections of 100 microCi of AIC are sufficient to cause complete regression of melanomas with volumes up to 300 mm3 without any observed side effects. Systemic TAT was less effective, with all tumours experiencing growth delay and limited inhibition of tumour growth. These data provide the basis for clinical trials of TAT in recurrent subcutaneous melanoma.

There can be little doubt that one of the most important problems in the management of cancer is control of metastatic disease. This objective must be achieved ideally with a systemic therapeutic modality that targets cancer cells and gives minimal collateral damage to critical normal cells. The efficacy of targeted cancer therapy relies on the ability of a toxin to be located in the target cancer cell. The ideal toxin is one that is active only in the cancer cell, and not in critical normal cells. Failing this, the next best approach is a toxin with a short effective lifetime to target early stage micrometastatic disease. This rules out chemical toxins, given that they remain effective until excreted from the body, and localization of dose to the cancer cell rules out beta-emitting radio-isotopes (RI). Alpha-emitting RI, however, are much more appropriate toxins because they are short-lived and because their cytotoxicity is the result of their high rate of energy loss and short range of the alpha particles. These radionuclides have properties that are particularly suited for the elimination of single cells in transit or small nests of cancer cells. In vitro and in vivo experiments with alpha RI show dramatic superiority over beta RI. Only a few nuclear hits are needed to kill cells, and the formation of metastatic lung lesions and subcutaneous lesions in mice can be inhibited by systemic administration of alpha emitters. But alpha RI have not been able to control solid tumours, for which beta RI are better suited. A small number of alpha-emitting radionuclides are currently under investigation. These are terbium (Tb)-149, astatine (At)-211, bismuth (Bi)-212 and Bi-213. Terbium-149 and At-211 both require accelerators in close proximity to the place of application. The Bi isotopes are produced by long-lived parents and, as such, can be obtained from generators. The first phase-1 dose escalation trial with Bi-213 radioimmunoconjugate (RIC) commenced in New York in 1997, and other trials are planned with At-211 RIC and At-211 methylene blue for melanoma. Actinium (Ac)-225 is obtained from the decay of thorium (Th)-229, which is a waste product in the enrichment of fissile Th-233. Alternative accelerator production routes are being investigated, beginning with the European Centre for Nuclear Research (CERN) GeV proton spallation source. The ready and low-cost availability of the Ac:Bi generator is an important element in the implementation of clinical trials for patients with poor prognoses but without evidence of metastatic disease.

The neutron transmission through 91 Zr was measured at both the 80 and 200 m stations of ORELA and, in combination with a capture measurement at .the 40 m. station, has resulted in resolved resonance parameters below. 20 keV bombarding , energy. The average s-wave resonance parameters obtained were as follows: the average level spacing

The neutron capture cross section of 139La has been measured with high energy resolution between 2· 5 and 90 ke V using the capture cross section facility at the 40 m station on the Oak Ridge Electron Linear Accelerator. Individual resonances were analysed to 15 keY and the average s-and p-wave radiative widths deduced were . = 55±6meV and p = 4O±7meV. The p-wave neutron strength function obtained was S1 = (0'30±0'1O)x 10-4 • The s-wave resonances decay strongly to final f-wave states via a postulated doorway state mechanism. The transition strengths for these decays are not correlated with the neutron widths of the initial states.