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

SUMMARYCurative 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.

Manufacturing and Fractional Cell Formation Using a New Binary Digit Grouping Algorithm with a Pwavroid Solution Explorer Toolkit

A new algorithm is presented in order to search for the optimal solution of the manufacturing and fractional cell formation problem. In addition, this paper introduces a new toolkit, which is used to search for the various candidate solutions in a periodic and a waving (diversified) manner. The toolkit consists of 15 tools that play a major role in speeding up the obtainment of the final solution as well as in increasing its efficiency. The application of the binary digit grouping algorithm leads to the creation of manufacturing cells according to the concept of group technology. The nonzero entries, which remain outside the manufacturing cells, are called exceptional elements. When a lot of such elements is obtained, an additional cell called fractional (or remainder) cell may be formed; the aim of which is to reduce their number. This algorithm was tested by using illustrative examples taken from the literature and succeeded to give better or at least similar results when compared to those of other well-known algorithms.

Nonsolvent Water in Human Erythrocytes

From the ability of a concentrated suspension of human erythrocytes to regulate the pH of unbuffered, anisotonic, external media it is possible to calculate the fractional cell volume in which chloride is dissolved. The difference between this volume and the total cell water gives the nonsolvent water (for chloride) of the cell. Nonsolvent water is less than 3% of the isotonic cell volume. The quantity of nonsolvent water per cell may increase as the cells shrink in hypertonic solutions.