Summary
SDX-308 and SDX-309 are potent indole-pyran analogues of SDX-101 (R-etodolac) which has anti-tumour activity unrelated to cyclooxygenase-2 inhibition. Their cytotoxic activity was further studied herein using a well-characterized human tumour cell-line panel containing ten cell lines, as well as in 58 primary tumour cell samples from a variety of diagnoses. The indole-pyran analogues of SDX-101 were in general considerably more active in both cancer cell lines and primary tumour samples. Low cross-reactivity with standard agents was observed, indicating a unique mechanism of action. No apparent influence on efficacy was observed via classical mechanisms of multidrug-resistance. SDX-101 and SDX-309 showed higher relative activity in haematological compared to solid tumour samples, while SDX-308 had pronounced solid-tumour activity. High SDX-308 cytotoxic efficacy was observed in non-small cell lung cancer, renal cancer and ovarian cancer samples, and also in chronic lymphocytic leukaemia. In conclusion, the indole-pyran analogues showed a favourable pharmacological profile and represent a potentially important new class of drugs for cancer treatment.
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The invaluable help of Sara Nissle, Lena Lenhammar, Christina Leek and Caroline Haglund is gratefully acknowledged.
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Salmedix Inc., San Diego, CA, USA is a subsidiary of Cephalon, Inc., Frazer, PA, USA.
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Lindhagen, E., Rickardson, L., Elliott, G. et al. Pharmacological profiling of novel non-COX-inhibiting indole-pyran analogues of etodolac reveals high solid tumour activity of SDX-308 in vitro. Invest New Drugs 25, 297–303 (2007). https://doi.org/10.1007/s10637-007-9049-4
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DOI: https://doi.org/10.1007/s10637-007-9049-4