Synergistic Drug Combinations Promote the Development of Resistance in Acute Myeloid Leukemia.

Unlabelled: Combination therapy is an important part of cancer treatment and is often employed to overcome or prevent drug resistance. Preclinical screening strategies often prioritize synergistic drug combinations; however, studies of antibiotic combinations show that synergistic drug interactions can accelerate the emergence of resistance because resistance to one drug depletes the effect of both. In this study, we aimed to determine whether synergy drives the development of resistance in cancer cell lines using live-cell imaging.

Ultrasensitive response explains the benefit of combination chemotherapy despite drug antagonism.

Most aggressive lymphomas are treated with combination chemotherapy, commonly as multiple cycles of concurrent drug administration. Concurrent administration is in theory optimal when combination therapies have synergistic (more than additive) drug interactions. We investigated pharmacodynamic interactions in the standard 4-drug 'CHOP' regimen in Peripheral T-Cell Lymphoma (PTCL) cell lines, and found that CHOP consistently exhibits antagonism and not synergy.

Drug independence and the curability of cancer by combination chemotherapy.

Combination chemotherapy can cure certain leukemias and lymphomas, but most solid cancers are only curable at early stages. We review quantitative principles that explain the benefits of combining independently active cancer therapies in both settings. Understanding the mechanistic principles underlying curative treatments, including those developed many decades ago, is valuable for improving future combination therapies.

Quantitative analysis of the yeast pheromone pathway.

The pheromone response pathway of the yeast Saccharomyces cerevisiae is a well-established model for the study of G proteins and mitogen-activated protein kinase (MAPK) cascades. Our longstanding ability to combine sophisticated genetic approaches with established functional assays has provided a thorough understanding of signalling mechanisms and regulation. In this report, we compare new and established methods used to quantify pheromone-dependent MAPK phosphorylation, transcriptional induction, mating morphogenesis, and gradient tracking.

A facilitated diffusion mechanism establishes the Dorsal gradient.

The transcription factor NF-κB plays an important role in the immune system, apoptosis and inflammation. Dorsal, a homolog of NF-κB, patterns the dorsal-ventral axis in the blastoderm embryo. During this stage, Dorsal is sequestered outside the nucleus by the IκB homolog Cactus.