Modulation of Dose Intensity in Aerodigestive Tract Cancers: Strategies to Reduce Toxicity

The population dynamics of cellular entry, traverse, and exit, through and from each phase of the cell cycle is coordinated throughout the day in the tissue of the human body. This coordination is particularly robust—ie, the daily peaks and valleys are particularly high and low—in tissues with the greatest average daily cellular proliferation. These tissues are also the most severely damaged by cancer treatments, most prominently cytotoxic drugs and ionizing irradiation.

Human bone marrow cells complete most of their DNA synthesis during the first half of the daytime hours.[1] The human rectal mucosa has a similar distribution of DNA synthesis that stretches more broadly across the daily waking hours.[2] The epithelial cells lining the human mouth also synthesize most of their DNA during the middle of a daily activity span.[3] Therefore, timing the administration of S-phase-active cytotoxic drugs should determine the amount of toxicity directed to these "dose-limiting" tissues. These dynamics also predict that giving such drugs during the usual waking hours of the day would be particularly damaging to these tissues.

In fact, doxorubicin(Drug information on doxorubicin) toxicity to human bone marrow is less severe and causes sixfold fewer episodes of neutropenic infection and bleeding when the drug is given prior to usual daily awakening, rather than in the evening.[4] The daily timing of fluorouracil(Drug information on fluorouracil) (5-FU), intra-arterial floxuridine (FUDR), 5-FU plus leucovorin, and 5-FU/leucovorin plus oxilaplatin, is responsible for five- to eightfold more bone marrow cell, oral epithelial cell, and colorectal mucosal cell damage when these agents peaks are administered in the daytime instead of the nighttime.[5-9]

Time of Day Treatment Is Given Enhances Anticancer Efficacy

Clearly, the timing of S-phase-active agents within the day can diminish toxicity. There is equally strong evidence that this strategy can simultaneously enhance anticancer efficacy. Optimally timing the administration of doxorubicin and cisplatin(Drug information on cisplatin) (Platinol) in women with advanced ovarian cancer increases the 5-year survival rate from 11% to 44%.[10] Optimally timing administration of 6-mercaptopurine (Purinethol) and methotrexate(Drug information on methotrexate) within each day raises the cure rate of childhood acute lymphoblastic leukemia from approximately 50% to 70%.[11] Optimally timing the 5-FU/leucovorin/oxilaplatin infusion doubles objective tumor responses in patients with metastatic colorectal cancer.[7]

In order for these benefits to be achieved, the drug susceptibility of human cancer must be coordinated within each day. Because these S-phase-active cytotoxic agents are cell-cycle-stage specific, this biology indicates that cell-cycle-phase traverse is also likely to be organized during each day in spontaneous human cancers (Figure 1).

Circadian Organization of Cancer Cell Division