NASHVILLE, Tennessee"Camptothecins have
radiosensitizing as well as cytotoxic effects, and combining a camptothecin
such as irinotecan with radiation on the right schedule might produce a
powerful antitumor regimen," according to Allan Chen, MD, PhD. Dr. Chen is
assistant professor of radiation oncology at Vanderbilt University Medical
Center in Nashville, Tennessee.
Dr. Chen reviewed previous phase I/II chemoradiation trials of
irinotecan (Camptosar) for non-small-cell lung cancer (NSCLC). "The
promising results of these early trials," he said, "indicate that
there is an urgent need to speed up understanding of the cytotoxic interaction
of radiation and the camptothecin drugs."
Combining chemotherapy with radiation presents a number of
potential advantages. One of these, Dr. Chen noted, is spatial cooperation:
chemotherapy offers systemic control, while radiation treats tumor sanctuary
sites. A second potential benefit is that chemotherapy reduces tumor burden at
the local primary tumor site. Some types of chemotherapy, including camptothecins, are also radiosensitizers and can increase the efficacy of a given
dose of radiation.
Attractive Therapeutic Target
Dr. Chen said that topoisomerase I is attractive as a
therapeutic target because it is elevated in both proliferating and quiescent
tumor cells and because targeting topoisomerase I can have both cytotoxic and
radiosensitizing effects. "Advances in studies of the molecular mechanism
of action of topoisomerase I as a therapeutic target provide a unique
opportunity for development of better cancer therapy," he said.
Cell killing by camptothecins requires active DNA synthesis.
Dr. Chen explained that topoisomerase I forms a transient covalent linkage with
the 3' end of the cleaved DNA during catalysis. Camptothecins trap this
reversible topoisomerase I-DNA cleavable complex and convert a DNA
topology-modifying activity into a DNA-breaking poison. This damages DNA
through interaction with ongoing DNA replication.
Radiation sensitivity varies during the mitotic cell cycle.
"Cells in G2-phase are the most sensitive to radiation. Those in S-phase
are the most resistant. Combining an S-phase-specific cytotoxic drug with
radiation theorectically should produce an additive effect," Dr. Chen
"Radiosensitization induced by camptothecins does not
occur if radiation is given prior to camptothecin treatment, which suggests
that it would not be effective to treat patients with radiation first followed
by chemotherapy," Dr. Chen said. "Topoisomerase I-directed
radiosensitization is schedule dependent and requires an intact stereospecific
interaction between drug and topoisomerase I." Topoisomerase I mediated
radiosensitization is also time dependent.
Proposed Explanatory Model
Dr. Chen proposed a model to explain topoisomerase I-mediated
radiosensitization (Figure 1). "After the camptothecin-trapped
topoisomerase I-DNA cleavable complex is formed, a collision with the DNA
replication apparently generates DNA damage that leads to radiosensitization
and cell death," he said. This process might be mediated by p53.
"Human cervical cancer HeLa cells are infected with the
high-risk human papillomaviruses (HPVs) types 16 and 18 and contain the
oncoproteins E6 and E7. The E6 protein encoded by the oncogenic HPVs targets
p53 for ubiquitin-dependent proteolysis and produces a relatively suppressed
p53 state in HeLa cells," Dr. Chen explained. "Campto-thecin produces
little or no radiosensitization in such cells." Studies of the human colon
cancer HCT-116 cell line compared to isogenic cells with p53 knocked out also
support this idea.
The heterodimeric Ku protein also contributes to the theory.
"The Ku protein binds to the ends of DNA breaks," Dr. Chen said.
"These proteins, which are the regulatory subunits of DNA-dependent
protein kinase, are involved in recombination and in nonhomologous end joining.
Ku-deficient cells are hypersensitive to ionizing radiation and to
topoisomerase II drugs." Ku-deficient cells are also less responsive to
topoisomerase I-mediated radiosensitization.
Dr. Chen proposed that topoisomerase I radiosensitization might
reduce the tumor cell’s ability to repair radiation-induced DNA damage that
would be sublethal and repairable in cells not treated with camptothecins.
"Our findings suggest that DNA damage plays a key role in
regulating topoisomerase I-mediated radiosensitization in mammalian
cells," Dr. Chen stated. "With a better understanding of the
mechanism of topoisomerase I-mediated radiosensitization, we might be able to
develop novel radiation sensitizers and chemoradiation regimens for cancer