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

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 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 (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 (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 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

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