Jane Chapman | PubMed Health

PubMed2006

Combination of cytosine deaminase with uracil phosphoribosyl transferase leads to local and distant bystander effects against RM1 prostate cancer in mice.

BACKGROUND: We aimed to evaluate the efficacy of gene-directed enzyme-prodrug therapy (GDEPT) using cytosine deaminase in combination with uracil phosphoribosyl transferase (CDUPRT) against intraprostatic mouse androgen-refractory prostate (RM1) tumors in immunocompetent mice. The product of the fusion gene, CDUPRT, converts the prodrug, 5-fluorocytosine (5FC), into 5-fluorouracil (5FU) and other cytotoxic metabolites that kill both CDUPRT-expressing and surrounding cells, via a 'bystander effect'. METHODS: Stably transformed andogen-independent mouse prostate cancer (PC) cells, RM1-CDUPRT, -GFP or GFP/LacZ cells were used. To assess the local bystander effects of CDUPRT-GDEPT, immunocompetent C57BL/6 mice implanted with cell mixtures of RM1-GFP/CDUPRT and RM1-GFP cells in different proportions intraprostatically were treated with 5FC. Pseudo-metastases in the lungs were established by a tail vein injection of untransfected RM1 cells. At necropsy, prostate weight/volume and lung colony counts were assessed. Tumors, lymph nodes, spleens and lungs were frozen or fixed for immunohistochemistry. RESULTS: CDUPRT expression in RM1-GFP/CDUPRT cells or tumors was confirmed by enzymic conversion of 5FC into 5FU, using HPLC. Treatment of mice bearing intraprostatic RM1-GFP/CDUPRT tumors with 5FC resulted in complete regression of the tumors. A 'local bystander effect' was seen, even though only 20% of the cells expressed CDUPRT. More importantly a significant reduction in pseudo-metastases of RM1 cells in lungs indicated a 'distant bystander effect'. Immunohistochemical evaluation of the treated tumors showed increased necrosis and apoptosis, with decreased tumor vascularity. There was also a significant increase in tumour-infiltration by macrophages, CD4+ T and natural killer cells. CONCLUSIONS: We conclude that CDUPRT-GDEPT significantly suppressed the aggressive growth of RM1 prostate tumors and lung pseudo-metastases via immune mechanisms involving necrosis and apoptosis.

Animals↗

PubMed2004

A comparative study of surface dose and dose distribution for intact breast following irradiation with field-in-field technique vs. the use of conventional wedges.

Dose to the contalateral breast is a traditional concern with the use of wedges in breast irradiation. A solution is to treat using field-in-field technique (segmental dose), which also provides a more uniform dose distribution to the irradiated volume. In this experiment, an anatomical phantom was scanned, planned, and treated using 3 different treatment techniques. Thermoluminescent dosimetry was used for verification and to measure skin surface dose on both breasts.

Breast↗

PubMed2002

TLD linearity vs. beam energy and modality.

Thermoluminescent dosimetry (TLD) is considered to be a valuable dosimetric tool in determining patient dose. Lithium fluoride doped with magnesium and titanium (TLD-100) is widely used, as it does not display widely divergent energy dependence. For many years, we have known that TLD-100 shows supralinearity to dose. In a radiotherapy clinic, there are multiple energies and modality beams. This work investigates whether individual linearity corrections must be used for each beam or whether a single correction can be applied to all beams. The response of TLD as a function of dose was measured from 25 cGy to 1000 cGy on both electrons and photons from 6 to 18 MeV. This work shows that, within our measurement uncertainty, TLD-100 exhibits supralinearity at all megavoltage energies and modalities.

Fluorides↗