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The Role of Amifostine as a Radioprotector

The Role of Amifostine as a Radioprotector

The article by Drs. Wasserman and
Brizel concludes that protection of normal tissue from side effects due to
radiotherapy will permit dose escalation and improve therapeutic efficacy and
treatment outcomes. Although this concept is sound in principle, its generalized
clinical application hinges critically on two controversial issues associated
with the use of all putative radioprotective agents: (1) the extent of a
reduction in normal tissue side effects afforded in a variety of dose-limiting
normal tissues, and (2) the potential for tumor protection.

Modulation of Radiation Response

Although a great deal of effort has been expended on various
approaches to sensitizing tumors to radiotherapy, attempts to protect normal
tissue from ionizing radiation damage have focused primarily on sulfhydryl-containing
compounds.[1] A lead agent initially developed at the Walter Reed Army Institute
of Research (WR-2721) and subsequently known as amifostine (Ethyol) protects
against sparsely ionizing radiation predominantly by scavenging free
radicals.[1,2]

The extent of this radioprotection is strongly dependent on
oxygen concentration, because the active metabolite of amifostine and oxygen
compete for free radicals.[2] Indeed, in a series of elegant preclinical
studies, Denekamp et al[3] clearly demonstrated that amifostine protection in
vivo is maximal at intermediate levels of oxygen. While the effective scavenging
of free radicals offers an attractive model for the protective action of agents
like amifostine, this explanation is likely to be an oversimplification, with
other complex factors undoubtedly being involved.[1,4]

Protection of Normal Tissues

Preclinical investigations have shown that, in general,
amifostine offers good protection to the hematopoietic system and salivary
glands (protection factors near 3), intermediate protection to organs such as
the kidneys and lungs (protection factors 1-2), and no protection to the
central nervous system.[1,4] In addition to this intertissue variability, the
extent of amifostine protection within normal tissues varies. The nature of the
variability is uncertain, but factors such as differences in tissue oxygen
tensions as well as amifostine distribution and pharmacodynamics may be
involved.[2,5]

As discussed by Drs. Wasserman and Brizel, the use of
amifostine may reduce the side effects of radiotherapy alone or in combination
with chemotherapy in a number of clinical settings. In the largest study to date—a
phase III randomized trial in head and neck cancer—Brizel et al[6] reported
that patients who received amifostine had reductions in both acute xerostomia of
grade 2 or greater (78% vs 51%, P < .0001) and chronic xerostomia of
grade 2 or greater (57% vs 34%, P < .002). Median saliva production was also
greater in patients treated with amifostine. However, no reduction in
radiation-induced mucositis was seen.

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