Response of human tumor cells to radiation and cytotoxic drugs

Abstract

Important differences between human cancers and experimental animal tumours limit the potential of the latter as models for cancer therapy research. This thesis describes the development of a clonogenic assay for human tumour cells, allowing for the first time the radiosensitivity and chemosensitivity of these to be measured in a way previously restricted to cells from experimental animal tumours and established tumour cell lines. The technique involves the use of agar in diffusion chambers implanted into murine peritoneal cavities, the mice acting both as "incubators" and as a source of nutrients for cell growth. Human tumour xenografts have been used for most experiments, although the use of the assay to clone cells from human tumours taken direct from the patient without xenograft passage has also been investigated. With this assay, the radiosensitivities of cells from several human tumours were measured, both in vitro and in vivo, and the dose survival curves so obtained provided information on the mechanisms underlying the clinical response of different human tumours to radiotherapy. The system was also used to demonstrate the enhancing effect of the radiosensitising drug Ro-07-0582 on the radiosensitivity of hypoxic tumour cells in vivo. Studies on the sensitivity of human tumour cells to cytotoxic drugs showed important differences compared with cells from experimental animal tumours, and some correlation was shown between cell survival in the assay and clinical response to chemotherapy. The advantages of this assay over those based on animal tumours as a tool to complement clinical cancer therapy research are discussed, and suggestions are proposed for its further use.