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AIM: To test the viability of a full-scale randomised comparison of two steroid doses given with radiotherapy for malignant spinal-cord compression (MSCC), to test Internet randomisation and to compare different functional outcome measures. MATERIALS AND METHODS: A log of screened patients at eight recruiting centres was maintained. Patients were randomised via the Superdex website to either 96 mg or 16 mg daily of dexamethasone. Radiotherapy treatment was 30 Gy in 10 fractions. Outcomes assessed used ambulation, Barthel Index ambulation, Functional Independence Measure (FIM) ambulation and Functional Improvement Score (FIS) at 1 month. RESULTS: One hundred and thirty-one patients were screened. Ninety-three (71%) were ineligible, 65% of these were because duration of prior steroid use was greater than 12 h, failure to meet strict definition of magnetic resonance imaging, defined MSCC, multi-level disease or previous spinal-cord compression treatment. Twenty of the 38 eligible patients were randomised, including seven outside standard office hours. There was a high rate of serious adverse events (n = 9), but only one was considered likely to be related to study medication. At baseline, 75% were ambulant, 70% had FIM ambulation scores greater than 5 and 50% had Barthel Index ambulation scores greater than 2. At day 28, including all randomised patients (by scoring four dead patients as non-ambulant), ambulation scores by the various definitions were 60%, 45% and 40%, respectively. For the 16 patients evaluable at day 28, the mean FIS was -1.4. Median survival was 69 days and 1-year survival 13%. CONCLUSION: Web randomisation was successful; however, the high ineligibility rate precludes a full-scale dexamethasone dose trial in Australia. Choice of measure of ambulation has potentially significant effects on outcomes and implications for the design of any future MSCC trials. Referral delays are of concern.

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We report the preparation and testing of a new alpha emitting radio-immunoconjugate (RIC) against acute myeloid leukaemia (AML) using CD33 positive monoclonal antibody WM-53 (specific for HL-60 cell line). Using cyclic anhydride of diethylenetriaminepentacetic acid (cDTPAa) as chelator, antibody was labeled with 213Bi (alpha), 149Tb (alpha), 153Sm (beta) and 152Tb (positron). In vitro testing showed high labeling efficiency (90-95%) and stability (11-19% leaching) with immunoreactivity virtually the same before and after labeling. DNA synthesis data and MTS cell survival were compared for all RICs. Only the alpha emitter was found to be capable of inhibiting DNA synthesis and had selective cell kill with activity as low as 2-3 microCi. The high stability and outstanding cytotoxicity of the 213Bi conjugate provides the basis for targeted alpha therapy for the control of metastatic and disseminated cancer such as AML.

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Terbium-152 (Tb-152) is of potential value as a radiotracer for radiolanthanides in positron emission tomography. We report the production of Tb-152 by heavy ion reactions at the ANU Tandem accelerator, and by the spallation method at the CERN proton accelerator using the on-line ISOLDE separator, obtaining microcurie and millicurie yields, respectively. After purification, a phantom image in PET is obtained which shows the feasibility of using Tb-152 for monitoring the kinetics of Tb-149 and other radiolanthanides. However, the current availability of this radioisotope will be restricted to major nuclear physics research centres.

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INTRODUCTION: Effective targeted cancer therapy requires high selectivity and cytotoxicity of the labelled product. We report the preparation and testing of anticolorectal cancer monoclonal antibody c30.6 radioimmunoconjugates (RIC) labelled with alpha-emitting Bismuth-213 and positron emitting Terbium-152 using two chelators, viz. Cyclic dianhydride of diethylenetriaminepentacetic acid (DTPA) and CHX-A" (a DTPA derivative). METHODS: Selectivity and stability of the RIC were tested in vitro (flow cytometry) and in vivo (biodistribution, organ/tumour uptake and retention). Cytotoxicity assays were carried out using tritiated thymidine uptake (inhibition of DNA synthesis) and MTS assay. RESULTS: High labelling efficiency (ranging between 89 and 91%) and stability over 2-5 half-lives of the isotopes were seen. Kidney retention was not seen in contrast to high uptake and retention of both conjugates in tumours. Flow cytometry studies showed high specificity of the antibody before and after labelling and this unchanged targeting behaviour was reflected in cytotoxicity assays. These assays showed that only alpha-labelled antibody could selectively kill the cancer cells for activities as low as 2-3 microCi. The study also revealed that free isotopes or isotopes bound to nonspecific antibodies did not kill cancer cells. CONCLUSION: The stability of the RICs and outstanding cytotoxicity of the alpha emitter, together with no kidney retention and high tumour uptake and retention of the radiolabel, offers a new approach for the potential control of colorectal cancer.

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Effective targeted cancer therapy requires high selectivity and cytotoxicity. To this end we have prepared and tested a new alpha-emitting radioimmunoconjugate (RIC) against malignant melanoma. The melanoma antibody 9.2.27 is specific for most melanoma cell lines. This antibody was labelled with an a emitter, bismuth-213 (213Bi), and a positron emitter, terbium-152 (152Tb), which is an analogue of the alpha-emitting radioisotope terbium-149. The chelators cDTPAa (a cyclic anhydride of diethylenetriamine pentacetic acid) and CHX-A" (a 2-(p-SCN-Bz)-cyclohexyl-DTPA ligand) were used in order to obtain high labelling yields for both isotopes with either chelator. The labelling efficiency with 213Bi was found to be 96% and 92% with cDTPAa and CHX-A", respectively. With 152Tb it was 93% and 89%, respectively. Serum stability studies showed 20% leaching with 213Bi over a period of 2.5 half-lives. For 152Tb the leaching was 13%. There was no difference in the melanoma cell binding of the labelled and unlabelled antibodies. DNA synthesis data were compared for both isotopes with either chelator. Based on these results, the therapeutic activity ratio for 213Bi a particles and 152Tb positrons for the same endpoint was calculated to be 120. The stability of the bismuth and terbium RICs, together with the outstanding cytotoxicity of the alpha emitter, provides the basis for a new approach to the potential control of micrometastatic melanoma.

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PURPOSE: Severe acute toxicity limits the effective use of radiotherapy in patients who are radiosensitive, and it is not usually possible to identify these radiohypersensitive (R-H) individuals before treatment commences. Five such R-H patients were detected over a 3-year period. We undertook this study to determine whether the severe acute radiohypersensitivity of these five individuals showed any correlation with cellular and molecular parameters known to be abnormal in radiosensitivity-related syndromes such as ataxia-telangiectasia (A-T). METHODS AND MATERIALS: Lymphoblastoid cells were isolated from fresh blood from the 5 R-H individuals who had previously demonstrated clinical R-H at least 9 months prior to sampling. Lymphoblastoid cell lines (LCLs) were established to determine the extent of postradiation chromosomal aberrations, cell cycle delay, cell proliferation, and tumor suppressor p53 protein stabilization. The polymerase chain reaction (PCR) and protein truncation (PTT) assays were used to test for the possibility of mutations in the gene mutated in A-T, termed ATM. RESULTS: LCLs derived from R-H subjects retained a significantly higher degree of radiation-induced chromosomal aberrations when compared to normal control LCLs. p53 stabilization by ionizing radiation appeared normal in all but one R-H subject. There was no evidence of A-T gene truncation mutations in any of the R-H subjects tested. CONCLUSIONS: All R-H subjects in this study had their cellular radiosensitivity confirmed by the chromosomal aberration assay. Delayed p53 stabilization at 4 hours postirradiation in one R-H subject suggested that different etiologies may apply in the radiohypersensitivity investigated in this study.

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