Ex vivo therapeutic index by drug sensitivity assay using fresh human normal and tumor cells.
Toxicity is a major deterrent to achieving substantial improvements in cancer management, since most anticancer drugs inadequately distinguish normal and neoplastic tissues. Improving the differential between beneficial and toxic effects of therapy--therapeutic index--is a major clinical objective, but therapeutic index for cytotoxic drugs is narrow. Fresh tumor and normal cells from 59 patients with acute myeloid leukemia, non-Hodgkin's lymphoma, ovarian cancer and cancers of unknown origin were tested for ex vivo drug sensitivity using apoptosis by morphology assays. Drugs tested included carboplatin, doxorubicin, vincristine, cytarabine, fludarabine, mafosfamide and etoposide. Therapeutic index was derived from the ratio of normal and tumor cell LC90s. Individual patient therapeutic index varied markedly for different drugs and drug therapeutic index varied from patient to patient ranging from extremely unfavourable (<0.001) through excellent (>1000) reflecting patient heterogeneity. Therapeutic index for each drug was consistent with clinical expectations. Significantly, there was no relationship between normal and tumor cell LC90s. We conclude that further laboratory and clinical evaluation is required but the derived ex vivo therapeutic index could enhance choice of chemotherapy by reducing toxicity and/or improving efficacy.
Bosanquet
Andrew G
AG
Bath Cancer Research, Royal United Hospital, Bath BA1 3NG, UK. agb@caltri.org
Bell
Philip B
PB
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents