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Novel Radiation Sensitizers Targeting Tissue Hypoxia

Novel Radiation Sensitizers Targeting Tissue Hypoxia

ABSTRACT: That hypoxic tissues are more resistant to the effects of radiation than well-oxygenated tissues has been known for many decades, and repeated in vitro demonstrations have confirmed that to achieve the same degree of cytotoxicity, hypoxic cells require about three times the radiation dose that well-oxygenated cells need. Hypoxic cell sensitizers enhance the tissue response to standard radiation, generally by mimicking the effects of oxygen, which induces the formation and stabilization of toxic DNA radicals. Although many hypoxic cell sensitizers like the nitroimidazoles have been evaluated in combination with radiation, these agents have had no or only minimal therapeutic impact due to either their limited potency or their toxicity at biologically relevant concentrations. This article reviews several new modalities that either increase oxygen delivery or sensitize hypoxic tissues. These modalities, all currently in early clinical evaluations, include: (1) tirapazamine, a bioreductive agent; (2) gadolinium texaphyrin, a hypoxic cell sensitizer with biolocalization properties using magnetic resonance imaging; (3) RSR13, an allosteric modifier of hemoglobin; and (4) bovine hemoglobin modified by the attachment of polyethylene glycol polymers.[ONCOLOGY 13(Suppl 5):61-70,1999]


Classic experiments performed in the early part of this century first
established that the absence of oxygen diminished the lethal effects
of radiation therapy. In general, under anaerobic conditions, the
radiation dose must be increased by a factor of 2.5 to 3 to achieve
the same degree of cytotoxicity that occurs under oxygenated
conditions. The radiosensitivity of cells increases as the partial
pressure of oxygen increases from 0 to 20 to 40 mmHg. Cells at oxygen
tensions of 20 to 40 mmHg demonstrate radiosensitivities that are
nearly equivalent to those of cells exposed to 100% oxygen.
Therefore, increasing oxygen pressure beyond this minimal level is
not necessarily beneficial.[1]

Hypoxic conditions are present in tumors and, based on experimental
studies, hypoxia appears to be a major cause of treatment failure
with radiation therapy and chemotherapy. In animal models, 10% to 20%
of tumor cells are generally found to be hypoxic.[2,3] Direct oxygen
measurements in human tumors have confirmed tumor hypoxia in
glioblastoma multiforme and in carcinomas of the breast, uterine
cervix, and head and neck.[2,3] Potential mechanisms of chronic or
transient hypoxia include obstruction of blood flow, inadequate or
defective (malignant) angiogenesis, and failure of cellular growth
control, allowing the cell population to outstrip the capacity of the
capillary blood supply. In general, tumor cells are oxygenated up to
a distance of about 150 mm from capillaries; beyond this distance,
tumor cells become oxygen-depleted and either die or survive in a
hypoxic state.[4-8] Since hypoxic cells are substantially more
resistant to radiation than are oxygenated cells, even a small
hypoxic fraction in a tumor will dominate the overall response to
radiation by increasing the probability that some viable tumor cells
will survive the treatment. Conversely, few hypoxic cells exist in
normal tissues. Therefore, therapies that increase the delivery of
oxygen to hypoxic cells are not expected to increase the toxicity of
radiation to normal tissues.

Several clinical studies have demonstrated that tumors with low
median partial pressures of oxygen have a higher in-field failure
rate after radiation therapy. For example, compared with
well-oxygenated tumors of similar size and stage, tumors of the
uterine cervix have been found to have a higher rate of recurrence if
the median partial pressure of oxygen in tissue is < 10 mmHg.[9] A
similar phenomenon has been noted in patients with head and neck cancer.[10]

In glioblastoma multiforme, a significant fraction of hypoxic cells
may partially account for the poor clinical results with radiation
therapy. In vitro, glioblastoma cells are as radiosensitive as cells
from tumors that radiation can cure, and yet local recurrence of
glioblastoma is universal. Therefore, the clinical radioresistance of
glioblastoma in vivo has been postulated to result from factors in
the tumor microenvironment, particularly hypoxia.[11] In addition,
experiments with rat 9L gliosarcoma have demonstrated that tumor
oxygen delivery is directly associated with the efficacy of
fractionated radiation.[12]

Intraoperative oxygen measurements in patients with glioblastoma have
confirmed significant tumor hypoxia. The median partial pressure of
oxygen in the tumor was 7.4 mmHg; 25% of all recorded measurements
were < 2.5 mmHg.[13] Although reoxygenation of hypoxic areas can
occur during fractionated radiation therapy, this process does not
eliminate the problem of hypoxia.[1,14,15] Measures to increase tumor
oxygenation are thus worthy of evaluation, particularly in patients
with glioblastoma multiforme.

Several therapeutic modalities intended to reduce tumor hypoxia in
humans have been evaluated in preclinical and clinical trials, and
the results of these investigations suggest that reducing the hypoxia
fraction does improve the efficacy of radiation therapy. Hyperbaric
oxygen in conjunction with radiation therapy resulted in greater
local tumor control and longer survival compared with conventional
therapy for squamous cell carcinoma of the head and neck and of the
uterine cervix.[16-19] Treatment with a fluorocarbon emulsion and
breathing carbogen (95% oxygen/5% carbon dioxide) during radiation
therapy was associated with an enhanced response rate to radiation in
patients with advanced squamous cell carcinoma of the head and
neck.[20] In addition, a study of patients with high-grade brain
tumors who received the fluorocarbon emulsion and breathed 100%
oxygen during radiation therapy yielded an encouraging proportion of
long-term survivors.[21]

Interestingly, these clinical studies have not demonstrated a
significant increase in the normal tissue complications of radiation,
although high rates of acute mucosal and skin reactions were noted.
Each of these measures has suffered from limitations that have
hampered its use in larger clinical trials where significant numbers
of patients could be enrolled, however. For example, hyperbaric
oxygen chambers are too expensive and cumbersome to use with
radiation therapy, and effective doses of hyperbaric oxygen are toxic.

Radiation sensitizers mimic the effects of oxygen to increase
radiation damage. The most common class of radiation sensitizer that
has been evaluated in clinical studies is the nitroimidazoles (eg,
misonidazole). However, their major limitation is neurotoxicity,
which has prevented the delivery of effective doses with conventional
daily fractionated radiation. One randomized trial suggested improved
survival when the radiosensitizer nimorazole was used to treat head
and neck cancer,[22] but thus far, radiation sensitizers have not led
to consistent improvements in the therapeutic index compared with
optimal fractionation schedules of radiation used alone.[23]

This report will consider four novel and highly specific therapeutics
designed to increase oxygen delivery or sensitize hypoxic tissues
during radiation therapy. These modalities, which are all in early
clinical investigations, include: (1) tirapazamine, which is a
hypoxia-selective cytotoxin that maintains its differential toxicity
relative to aerobic cells at higher oxygen concentrations than do
other bioreductive agents; (2) gadolinium texaphyrin, an “easy
to reduce” metallotexaphyrin that is readily capable of
“capturing” hydrated electrons and thus increasing the
concentration of hydroxyl radicals available after exposure to a
given dose of ionizing radiation; (3) RSR13, an allosteric modifier
of human hemoglobin that facilitates oxygen unloading at low partial
pressures of oxygen; and (4) bovine hemoglobin modified with
polyethylene glycol (PEG) to enhance the oxygen-carrying capacity of
human blood.


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