In vitro and preclinical targeted alpha therapy of human prostate cancer with Bi-213 labeled J591 antibody against the prostate specific membrane antigen.

Limited options for the treatment of prostate cancer have spurred the search for new therapies. One innovative approach is the use of targeted alpha therapy (TAT) to inhibit cancer growth, using an alpha particle emitting radioisotope such as (213)Bi. Because of its short range and high linear energy transfer (LET), alpha-particles may be particularly effective in the treatment of cancer, especially in inhibiting the development of metastatic tumors from micro-metastases. Prostate-specific membrane antigen (PSMA) is expressed in prostate cancer cells and the neovasculature of a wide variety of malignant neoplasms including lung, colon, breast and others, but not in normal vascular endothelium. The expression is further increased in higher-grade cancers, metastatic disease and hormone-refractory prostate cancer (PCA). J591 is one of several monoclonal antibodies (mabs) to the extracellular domain of PSMA. Chelation of J591 mab with (213)Bi forms the alpha-radioimmunoconjugate (AIC). The objective of this preclinical study was to design an injectable AIC to treat human prostate tumors growing subcutaneously in mice. The anti-proliferative effects of AIC against prostate cancer were tested in vitro using the MTS assay and in vivo with the nude mice model. Apoptosis was documented using terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridinetriphosphate [dUTP] nick end-labeling (TUNEL) assay, while proliferative index was assessed using the Ki-67 marker. We show that a very high density of PSMA is expressed in an androgen-dependent human PCA cell line (LNCaP-LN3) and in tumor xenografts from nude mice. We also demonstrate that the AIC extensively inhibits the growth of LN3 cells in vitro in a concentration-dependent fashion, causing the cells to undergo apoptosis. Our in vivo studies showed that a local AIC injection of 50 microCi at 2 days post-cell inoculation gave complete inhibition of tumor growth, whereas results for a non-specific AIC were similar to those for untreated mice. Further, after 1 and 3 weeks post-tumor appearance, a single (100 microCi/100 microl) intra-lesional injection of AIC can inhibit the growth of LN3 tumor xenografts (volume<100 mm(3)) in nude mice. Tumors treated with AIC decreased in volume from a mean 46+/-14 mm(3) in the first week or 71+/-15 mm(3) in the third week to non-palpable, while in control mice treated with a non-specific AIC using the same dose, tumor volume increased from 42 to 590 mm(3). There were no observed side effects of the treatment. Because of its in vitro cytotoxicity and these anti-proliferative properties in vivo, the (213)Bi-J591 conjugate has considerable potential as a new therapeutic agent for the treatment of prostate cancer.

Fission converter and metal-oxide-semiconductor field effect transistor study of thermal neutron flux distribution in an epithermal neutron therapy beam.

The depth distribution of the thermal neutron flux is a major factor in boron neutron capture therapy (BNCT) in determining the efficiency of cell sterilization. In this paper the fission detector method is developed and applied to measure the in-phantom thermal neutron flux depth distribution. Advantages of the fission detector include small size, direct measurement of thermal neutron flux in a mixed radiation field of BNCT beam, self-calibration, and the possibility of on-line measurement. The measurements were performed at epithermal a BNCT facility. The experimental results were compared with the thermal neutron flux calculated by the Monte Carlo method and found to be in good agreement.

Changes in body composition during breast cancer chemotherapy with the CMF-regimen.

Weight gain is a reported problem associated with adjuvant chemotherapy for breast cancer and often generates psychosocial stress in women [1]. It also may affect prognosis and survival. Changes in body composition and weight during chemotherapy, particularly adjuvant treatment of breast carcinoma, have been previously reported [1-3]. Multiple reasons for this weight gain have been suggested though few theories have been scientifically validated [4]. The aim of this study was to investigate body composition and its relationship to weight change associated with the CMF-based breast cancer chemotherapy protocols. Total body nitrogen (TBN), body fat, total body water (TBW), and anthropometric measurements were conducted on 25 female out-patients (median age 47, range 26-70 years) receiving adjuvant CMF-based chemotherapy for breast cancer. Total body nitrogen was measured using the In Vivo Neutron Capture Analysis (IVNCA) technique (on day 1 of cycles 2-6) and TBP was calculated by multiplying TBN by 6.25 [5]. Nitrogen Index (NI) was calculated by expressing TBN as a percentage of normal. There was a significant increase in mean body weight during chemotherapy of 2.35 kg (p < 0.0001). Serial measurements showed no significant change in mean TBN, NI, or percentage body fat. Break down of body weight showed a significant increase in mean TBW of 0.79 kg (p = 0.003) and mean fat mass of 1.49 kg (p = 0.008). We conclude that weight gain observed during adjuvant chemotherapy for breast carcinoma is primarily due to an increase in fat and TBW.

Selective uptake of boronated low-density lipoprotein in melanoma xenografts achieved by diet supplementation.

The lipid core of human plasma low-density lipoprotein (LDL) was extracted using hexane and the LDL reconstituted with the addition of n-octyl-carborane. Biodistribution studies of the boronated LDL were performed in BALB/c mice bearing subcutaneous Harding-Passey melanoma xenografts. When diet supplementation with coconut oil and cholesterol for 21 days and regular dosing with hydrocortisone for 7 days before the studies was used to down-regulate the liver LDL receptors and the adrenal receptors, respectively, the tumour-blood boron concentration ratio of 5:1 was achieved.

Body protein in prepubertal children with phenylketonuria.

OBJECTIVE: To assess body protein and protein deposition in prepubertal children with phenylketonuria (PKU). DESIGN: Cross-sectional study with nested longitudinal cohort. SETTING: A tertiary referral paediatric hospital. SUBJECTS: 37 PKU patients (3.9-11.0 years) and 27 unselected healthy controls (4.0-11.5 years) of whom 29 PKU patients and 17 controls were followed longitudinally. INTERVENTIONS: All had measurements of height, weight, body fat and total body nitrogen (TBN) by neutron capture analysis; PKU patients and their unaffected siblings (n = 16) also had measurements of four day weighed food record and plasma amino acids by HPLC. RESULTS: The children with PKU compared with the controls were significantly shorter (height SD score -0.42 +/- 0.89 vs 0.17 +/- 0.94, respectively, P < 0.02) and had a lower TBN (575 +/- 200 vs 710 +/- 215g, respectively, P < 0.02). TBN in the controls was significantly correlated with lean body mass (LBM), weight, height and age (r = 0.97, 0.95, 0.95, 0.88, respectively, P < 0.001). The children with PKU had significantly lower TBN when predicted from LBM, weight and age (93%, 92%, 92% of predicted, respectively), but normal TBN predicted from height (102% of expected). The annual accretion of nitrogen was similar for the PKU and controls (86 +/- 45 and 77 +/- 58 g/y, respectively). There was no difference between the two groups in protein intake or plasma amino acids except for phenylalanine. CONCLUSION: The children with PKU had a deficit in height and body protein despite a normal to higher accretion of protein. If the deficit occurs early in life, amino acid supplementation and other nutritional practices used at this time need to be reviewed.