A significant variation in intrinsic radiosensitivity of breast cancer patients' dermal fibroblasts was observed. However, the degree of radiosensitivity did not show a significant correlation with fibrosis development. This indicates that the use of fibroblast radiosensitivity will have a limited usefulness for predicting fibrosis following breast irradiation.

The aim of this study was to determine whether significant inter-individual differences exist between skin fibroblast strains obtained from radiotherapy patients in both radiation-induced differentiation and collagen production in vitro, for use as potential parameters for a predictive assay for fibrosis following radiotherapy in patients. Morphological cell differentiation was determined 7 days after irradiation in seven early-passage primary human fibroblast cell strains and correlated with cell survival. Collagen production was measured in two cell strains by flow cytometry and incorporation of 3H-proline. There was a wide variation in the extent of radiation-induced differentiation for the seven cell strains, each showing a dose-related increase. The correlation between induced differentiation and cell survival was poor (r = 0.64) but statistically significant (p < 0.01). Collagen synthesis increased 7 days after irradiation for one cell strain (HF-48), as measured by incorporation of 3H-proline, but not in radiation sensitive AT-1 cells. The collagen I content of the two cell strains was assessed by flow cytometry but no significant differences were observed between the strains tested or with increasing dose. In conclusion, marked variations in radiation-induced fibroblast differentiation were observed between patients, this being an important criterion for a predictive assay.

We used a poly-lactide-co-glycolide polymer (PLAGA 50:50) to formulate cisplatin (cDDP) into microspheres designed for intravascular administration. Two systems were developed. PLAGA-coated albumin microspheres and microspheres consisting of PLAGA only. PLAGA-coated microspheres displayed a mean diameter of 31.8 +/- 0.9 microns and a payload of 7.5% cDDP (w/w). Solid PLAGA microspheres exhibited a mean diameter of 19.4 +/- 0.6 microns and a payload of 20% cDDP. Release characteristics and in vitro effects on L1210 leukemia and B16 melanoma cell lines were investigated. Both types of microsphere overcame the initial rapid release of cDDP (burst effect), and PLAGA-coated albumin microspheres also showed a lag phase of approximately 30 min before cDDP release began. PLAGA-coated albumin microspheres released most of their payload through diffusion, and the coating eventually cracked after 7 days' incubation in saline supplemented with 0.1% Tween at 37 degrees C, enabling the release of any cDDP remaining. Effects of platinum, pre-released from PLAGA-coated albumin microspheres on the in vitro growth of L1210 cells were comparable with those of standard formulations (dissolved) of cDDP. Material released from non-drug-loaded PLAGA microspheres had no effect on L1210 cell growth, suggesting the absence of cytotoxic compounds in the matrix. The colony-forming ability of B16 cells was also equally inhibited by standard cDDP and pre-released drug. These studies show that formulation of cDDP in PLAGA-based microspheres prevents the rapid burst effect of cDDP seen in previous preparations and offers an improved system of administration for hepatic artery infusion or adjuvant therapy, enabling better clinical handling and the promise of a higher ratio of tumour tissue to normal tissue.

Summary Blood pharmacokinetics and tissue distribution of 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU), a boron carrier with postulated melanin-seeking properties for boron neutron capture therapy, were determined in C57/BL mice with subcutaneous pigmented or non-pigmented B16 melanomas. Borocaptate sodium (BSH) was used as a boron compound without melanin-seeking properties in a comparative biodistribution study in the same animal tumour models. Administration of single doses showed that BPTU was retained better in the pigmented B16 tumour than in the non-pigmented variant. BPTU was found in large concentrations in kidney and liver. Brain boron was approximately 10-fold lower than tumour boron. On a molar basis, BPTU demonstrated higher affinity for B16 tumours than BSH. Owing to solubility limits, tumour boron concentrations in this mouse study were too low for effective application of BNCT. However, the high tumour-to-blood and tumour-to-normal tissues ratios indicate that, with appropriate formulation, BPTU could be a promising candidate for clinical BNCT.The primary goal of boron neutron capture therapy (BNCT) at the present time is to achieve more effective treatments for glioma and melanoma than conventional radiotherapy (Allen et al., 1989;Slatkin, 1991). The selective accumulation of "'B-containing compounds in tumours and subsequent irradiation with low-energy (thermal) neutrons form the basis of BNCT. The short track lengths of`'B(n,a)7Li fission products (9 and 5 iLm for a and 7Li respectively) offer partial restriction of the radiation dose to the "'B-containing cells. Additional advantages owing to the high-LET (linear energy transfer) character of the emitted radiation are higher biological efficacies compared with photons or X-rays and less effect of hypoxia or cell cycle distribution on the therapeutic effect. The relatively high resistance of melanomas for photon therapy and the presence of a biochemical rationale for boron targeting explain the efforts made in this area Madoc Jones et al., 1990). The often high rate of melanogenesis in melanoma cells has led to the development of several boron drugs with melanoma-seeking capacity.The L-isomer of boronphenylalanine (BPA) is taken up by melanoma cells both in vitro and in vivo (Ichihashi et al., 1982; Coderre et al., 1987;Allen et al., 1992;Packer et al., 1992). Animal studies on BNCT efficacy and normal tissue tolerance with BPA have also been performed (Coderre et al., 1991; Hiratsuka et al., 1991). Although the uptake of BPA in melanoma cells is well accepted, incorporation of boron into melanin might not occur, resulting in poor retention. Boronated thiouracils that enter the melanogenesis pathway at a different point from BPA have been recently synthesised, aiming at boron incorporation into the melanin for better retention (Tjarks & Gabel, 1991). We have found previously that 5-dihydroxyboryl-6-propyl-2-thiouracil (BPTU) and not boronthiouracil (BTU) was retained in vitro in melanotic B16 cells, while BPTU failed to be retained in th...

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