Chronotherapy of Early Colon Cancer: Advantage of Morning Dose Schedules

Abstract

Colon adenomas with proliferating mutant cells may progress to invasive carcinomas. Proliferation of cells in human colorectal tissue is circadian, greater in the interval 4 to 12 hours after midnight than 16 to 24 hours after midnight. We have tested the hypothesis that chemotherapy administered during the time of greater cell proliferation will be more effective than chemotherapy administered during the time of lesser proliferation. An agent-based computer model of cell proliferation in colon crypts was calibrated with measurements of cell numbers in human biopsy specimens. It was used to simulate cytotoxic chemotherapy of an early stage of colon cancer, adenomas with about 20% of mutant cells. Chemotherapy doses were scheduled at different 4-hour intervals during the 24-hour day, and repeated at weekly intervals. Chemotherapy administered at 4 to 8 hours after midnight cured mutant cells in 100% of 50 trials with an average time to cure of 7.82 days (s.e.m. = 0.99). In contrast, chemotherapy administered at 20 to 24 hours after midnight cured only 18% of 50 trials, with the average time to cure of 23.51 days (s.e.m. = 2.42). These simulation results suggest that clinical chemotherapy of early colon cancer may be more effective when given in the morning than later in the day.

Keywords: Chronotherapy; chemotherapy; circadian rhythm; colorectal neoplasm; computer simulation.

Figure 1.

Flowchart of the main steps in the modification of the agent-based model of cell proliferation in human colon crypts to account for circadian proliferation of mutant cells, and the response of mutant cells to cytotoxic therapy applied at different times of day. Simulation results indicate the probability to cure mutant cells, and the length of time to cure mutant cells, when cytotoxic therapy is applied at different times of day.

Figure 2.

Circadian rhythm of cell proliferation in humans, and fit to cosine function. The data for a 24-h interval is repeated for illustration. Light line: DNA synthesis determined by the incorporation of tritiated-thymidine in rectal mucosal samples from 16 human subjects. Each point is the mean of samples in a 2-h interval. The s.e.m. are indicated for the 24-h on the left. Heavy line: Cosine function fit to the experimental data using the Cosinor method. The cosine function was used to determine the rate of cell proliferation at different times of day in the model.

Figure 3.

Probability that patients are cured with 4-h of chemotherapy starting at different times after midnight. For each time there were 50 simulation runs. The distribution is not uniform, chi-squared test, P < .0001.

Figure 4.

The length of time (days) that mutants are cured after 4-h of chemotherapy starting at different times after midnight. Mean and s.e.m., N = 50. The lengths of time to cure mutants for chemotherapy starting at 8- and 20-h after midnight are significantly different, t-test assuming unequal variances. P < .0001.

Figure 5.

The length of time (days) to cure after 4-h of chemotherapy starting at 20-h after midnight (top) and at 8-h after midnight (bottom). For chemotherapy starting at 20-h, 38% (19/50) of the runs had all mutants cured, distributed at 14, 21, 28, and 35 days. For chemotherapy at 8-h after midnight, 90% (45/50) of the runs were cured distributed most within 1 day, with the remainder cured at 7 days, and 14 days.