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.

Parameters affecting the ex vivo cytotoxic drug sensitivity of human hematopoietic cells.

The drug sensitivity of normal cells provides a baseline for determining the therapeutic index, and therefore the effectiveness, of cytotoxic drugs, yet little is known about the factors that affect normal cell chemosensitivity. Some parameters are known to have a profound effect on tumor cell sensitivity. The purpose of this study was to determine how cytotoxic drug sensitivity of hematopoietic cells isolated from cancer patients was affected by various parameters. These included previous chemotherapy (yes or no), sex, age, tumor type (leukemias or solid tumors), sample source (blood, bone marrow, serous effusions, or tumor biopsies) and predominant cell lineage (lymphoid, myeloid, macrophage, or mixed). Mononuclear cells isolated from blood, bone marrow, serous effusions, and tumor biopsies were incubated for four days with a median of 16 drugs. The differential staining cytotoxicity assay, an ex vivo apoptotic drug sensitivity test in which cell survival is determined morphologically, was used to assess normal hematopoietic and tumor cell response to cytotoxic drugs. One hundred forty-six specimens yielded hematopoietic cell chemosensitivity results with 3-36 drugs. Compared with tumor cells, there was far less interpatient variation in chemosensitivity of hematopoietic cells. Mean hematopoietic cell drug sensitivity showed little variation due to previous chemotherapy, sex, age, tumor type, and sample source or cell lineage. We therefore concluded that cytotoxic drug sensitivity of hematopoietic cells from a variety of sources could be used for assessment of therapeutic index. Drug therapeutic index results are a valuable tool in identifying novel cytotoxic agents and individually tailored chemotherapy regimens.