The Microculture-Kinetic (MiCK) Assay: The Role of a Drug-Induced Apoptosis Assay in Drug Development and Clinical Care

Abstract

A drug-induced apoptosis assay, termed the microculture-kinetic (MiCK) assay, has been developed. Blinded clinical trials have shown higher response rates and longer survival in groups of patients with acute myelocytic leukemia and epithelial ovarian cancer who have been treated with drugs that show high apoptosis in the MiCK assay. Unblinded clinical trials in multiple tumor types have shown that the assay will be used frequently by clinicians to determine treatment, and when used, results in higher response rates, longer times to relapse, and longer survivals. Model economic analyses suggest possible cost savings in clinical use based on increased generic drug use and single-agent substitution for combination therapies. Two initial studies with drugs in development are promising. The assay may help reduce costs and speed time to drug approval. Correlative studies with molecular biomarkers are planned. This assay may have a role both in personalized clinical therapy and in more efficient drug development. Cancer Res; 72(16);

Programmed cell death in aging

“…Most cancer chemotherapies, including ionizing radiation, are thought to act by hyper-stimulating the otherwise suppressed PCD pathways, including activating any remaining p53 (Stegh, 2012; Zhao et al, 2012). Consistent with this idea, the efficiency of induction of apoptosis by chemotherapy has been shown to correlate with clinical outcomes for several cancers (Bosserman et al, 2012). However, it should be noted that other studies suggest that, at least for certain cell types, the tumor-suppressive function of p53 is independent of transcriptional induction of apoptosis, and instead may involve p53 regulation of DNA repair and/or metabolism(Valente et al, 2013).…”

A Small Molecule that Induces Intrinsic Pathway Apoptosis with Unparalleled Speed

“…Raptinal-induced apoptosis challenges the widely held belief that apoptosis takes a minimum time of several hours (Goldstein et al, 2000). A rapid apoptotic phenotype can have important implications in drug development and treatment regimens as supported by recent studies suggesting the rate and extent of apoptotic induction in cell culture can be used to identify effective regimens and drug combinations for the treatment of cancer patients in the clinic (Bosserman et al, 2012; Strickland et al, 2013). …”

Microfluidic Biopsy Trapping Device for the Real-Time Monitoring of Tumor Microenvironment

“…Personalized information can better assist doctors to select effective chemotherapy regimens for individual patients. Various chemosensitivity assays used in clinic have been comprehensively reviewed [11, 12] but have been developed to assay chemosensitivity on an isolated subset of cells expanded from a tumor biopsy and cultured as a monolayer on a well plate. To accurately assess the efficacy of chemotherapy among patients, a physiologically meaningful model should be used that incorporates not only the cancer cells but also its microenvironment with its supporting stromal components.…”

“…More importantly, the cell culture conditions found in a conventional cell culture model may not be homogenous, primarily because of static and concentrated chemical gradients within the cell culture system. Chemosensitivity assays that use primary cultures of cells grown from surgically excised tumor specimens and incubated with a panel of therapeutic drugs are also performed in static conditions, often in a well-plate configuration [11, 12]. Limiting the tumor samples to a static environment hampers full nutritive support confounding the true efficacy of the drug treatment.…”