Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study
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The effectiveness of cancer chemotherapy is limited by intra-tumor heterogeneity, the emergence of spontaneous and induced drug-resistant mutant subclones, and the maximum dose to which normal tissues can be exposed without adverse side effects. The goal of this project was to determine if intermittent schedules of the maximum dose that allows colon crypt maintenance could overcome these limitations, specifically by eliminating mixtures of drug-resistant mutants from heterogeneous early colon adenomas while maintaining colon crypt function.
A computer model of cell dynamics in human colon crypts was calibrated with measurements of human biopsy specimens. The model allowed simulation of continuous and intermittent dose schedules of a cytotoxic chemotherapeutic drug, as well as the drug’s effect on the elimination of mutant cells and the maintenance of crypt function.
Colon crypts can tolerate a tenfold greater intermittent dose than constant dose. This allows elimination of a mixture of relatively drug-sensitive and drug-resistant mutant subclones from heterogeneous colon crypts. Mutants can be eliminated whether they arise spontaneously or are induced by the cytotoxic drug.
An intermittent dose, at the maximum that allows colon crypt maintenance, can be effective in eliminating a heterogeneous mixture of mutant subclones before they fill the crypt and form an adenoma.
KeywordsDrug resistance Heterogeneity Dose schedules Intermittent Colon cancer Adenoma Crypt
We thank Rafael Bravo for writing the code for the original colon crypt model, Dr. Steven Schiff for providing human biopsy specimens, members of the Division of Life Sciences IT Support Group for computer services, RUCore staff for file archive services, and Uri Wilensky for making available the NetLogo open-source application.
DEA. conceived the project, analyzed and interpreted the simulation results, and wrote the manuscript. SV and DEA. carried out the simulations. JO and DEA wrote the revised the code. All authors approved the manuscript.
Compliance with ethical standards
The Human Genetics Institute of New Jersey, the New Jersey Breast Cancer Research Fund, and the Rutgers Cancer Institute of New Jersey (PA30CA072720).
Conflict of interest
The authors declare that they have no conflict of interest.
D.E.A. obtained coded de-identified slides containing sections from biopsies of the sigmoid colon of normal patients enrolled in a clinical research study of Dr. Steven Shiff, Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey. Individualized information about the identity of the subjects and specific clinical information were not made available to D.E.A. Dr. Shiff received approval Reference Number 4611 from the Institutional Review Board for Research Study Involving Human Subjects. The approved protocol included informed consent of participants.
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