Ashmore, Sally Michele; (1998) Studies on drug resistance in adult human malignant astrocytoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The prognosis of malignant astrocytomas in adults is very poor. The use of surgery, radiotherapy and chemotherapy can only modestly, yet significantly, prolong survival. However, whilst adjuvant chemotherapy has the potential to increase patient survival this is limited by the marked resistance to cytotoxic drugs which these tumours display, the mechanisms of which are unknown. Drug resistance has been examined using two sources of cellular material, short-term cell cultures derived from biopsy material and archival paraffin embedded material taken at the time of diagnosis and again at the time of eventual tumour recurrence. Although cultures displayed wide variation in sensitivity to two cytotoxic drugs, vincristine and doxorubicin, this did not correlate with expression of cell surface glycoproteins associated with drug resistance like P-glycoprotein and MRP (multi-drug resistance associated protein). However, overexpression of p53 protein did correlate with marked sensitivity to vincristine and an unrelated drug CCNU, but not with doxorubicin. Clinical follow-up of the patients from whom the cultures were derived suggested that overexpression of p53 correlated with short survival times, and p53 expression appeared to be a better prognostic factor than chemosensitivity in vitro or administration of adjuvant chemotherapy. The cells that repopulate the recurrent tumours often differ in their chromosomal number and chemosensitivity. In paraffin wax embedded material derived from paired samples taken at diagnosis and again at recurrence for the same patient, the cells derived from recurrent tumour appeared to contain more copies of chromosome 7, but not chromosome 22, as evidenced by FISH.

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