Effective chemotherapy of heterogeneous and drug-resistant early colon cancers by intermittent dose schedules: a computer simulation study.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Genetics and Cancer Institute of New Jersey, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854-8082, USA. axelrod@biology.rutgers.edu.
David E
http://orcid.org/0000-0002-0912-3870
DE
Axelrod
Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ, 08854, USA.|Department of Molecular Biology and Biochemistry, Rutgers University, 604 Allison Road, Piscataway, NJ, 08854-8082, USA.
Sudeepti
S
Vedula
Department of Biomedical Engineering, Rutgers University, 599 Taylor Road, Piscataway, NJ, 08854, USA.
James
J
Obaniyi
D058739:Aberrant Crypt Foci; D000236:Adenoma / Q000188:drug therapy*; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use*; D002138:Calibration; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003198:Computer Simulation; D018450:Disease Progression; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D006801:Humans; D009154:Mutation
D000970:Antineoplastic Agents
Adenoma; Colon cancer; Crypt; Dose schedules; Drug resistance; Heterogeneity; Intermittent