Nov 5, 2018

A curative combination therapy for lymphomas achieves high fractional cell killing through low cross-resistance and drug additivity but not synergy

BioRxiv : the Preprint Server for Biology
Adam C PalmerPeter K Sorger

Abstract

Curative cancer therapies are uncommon and nearly always involve multi-drug combinations developed by experimentation in humans; unfortunately, the mechanistic basis for the success of such combinations has rarely been investigated in detail, obscuring lessons learned. Here we use isobologram analysis to score pharmacological interaction, and clone tracing and CRISPR screening to measure cross-resistance among the five drugs comprising R CHOP, a combination therapy that frequently cures Diffuse Large B-Cell Lymphomas. We find that drugs in R CHOP exhibit very low cross-resistance but not synergistic interaction; together they achieve a greater fractional kill according to the null hypothesis for both the Loewe dose-additivity model and the Bliss effect-independence model. These data provide direct evidence for the 50-year old hypothesis that a curative cancer therapy can be constructed on the basis of independently effective drugs having non-overlapping mechanisms of resistance, without synergistic interaction, which has immediate significance for the design of new drug combinations.

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Mentioned in this Paper

Combination Drug Therapy
DDIT3 wt Allele
DDIT3 gene
Analysis of Substances
Cancer Treatment
Pharmacologic Substance
Resistance Process
Screening Generic
Curative - Procedure Intent
Clustered Regularly Interspaced Short Palindromic Repeats

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