B194
Activity of rapamycin against fresh human tumour and normal cells ex vivo
Andrew G Bosanquet1, Justin Durant1, Sheila M Scadding1, Claudius E Rudin 2
1Bath Cancer Research, Bath, UK, 2Royal Devon and Exeter Hospital, Exeter, UK
Background
The mTOR inhibitor rapamycin (sirolimus, Rapamune (Wyeth)) and its analogues have proven clinical activity against renal cell carcinoma and B cell lymphomas. We provide Individualised Tumour Response Testing (ITRT) as a service to physicians and their patients – results have prognostic significance and are predictive of response and survival. Our aim was to compare the activity of rapamycin against fresh human tumour cells with that of the standard cytotoxics tested.
Method
Cytotoxicity of ITRT Rapamycin (2-32 ug/ml) and 10 other drugs was assessed by TRAC assay (Tumour Response to Anti-neoplastic Compounds). Cells from a normal control were also repeatedly tested.
Results
Cells from 63 leukaemias and lymphomas were tested – 56 with B cell malignancies (CLL in 42; all previously treated). There was a steep dose-response curve for rapamycin. Greatest activity (best average therapeutic index (TI)) was found for non-Hodgkin lymphomas and CLL; for other specimens it averaged 1.0. Rapamycin was most cross-resistant with chlorambucil and doxorubicin; less so with methylprednisolone and fludarabine. Two of seven CLL samples resistant to fludarabine were very sensitive to rapamycin. Patient-to-patient variation was small, suggesting that activating mutations in the mTOR pathway do not appear to be common critical oncogenic events in B cell malignancies.
Conclusion
Together with the previously demonstrated clinical responses in B cell lymphomas these results show that rapamycin has potential efficacy in pre-treated CLL, with some activity in fludarabine-resistant samples.
