4631370551

350 J. KUDUK.-JAWORSKA

ABSTRACT

This review describes some current approaches in using metal compounds to modulate the response of tumors and normal tissues to celi killing by ioni-zing radiation. It is known that many tumors contain necrotic, oxygen-def-ficient areas which show diminished radiation sensitivity. Normal tissues contain mostly oxic cells; so antihypoxia therapies should be relatively tu-mor-specific. The biochemical role of oxygen is in fixing, or making permanent, the damage done to the critical DNA target. Radiation can damage DNA either by direct interaction or indirectly by ionizing created in nearby water molecules. The resulting DNA State depends on a competition between oxygen for damage fixation and reducing species, such as hydrated electron or thiol compounds (—SH), for Chemical restitution ([10] and ref).

Approaches to Chemical modification include use of (1) “electron-affinic” sensitizers which act as oxygen mimetics; (2) thiol-binding agents which pro-long life and action of OH' radical that is the most cytotoxic water radiolysis product; and (3) DNA-binding agents which may inhibit repair processes [1],

An ideał radiosensitizer would be nontoxic to aerobic cells. The classic radiosensitizers are the nitroheterocycles as exemplificd by nitrofurans and nitroimidazoles. Their nitro groups are “electron-affinic” and hence may internet with damage on DNA induced by radiation in a manner analogous to oxygen [1, 51].

Metal complexes would appear to represent ideał candidates for studies of their potential sensitizing properties, but only fcw such studies have been car-ried out. Metal complexes which exhibit greater radiosensitizmg properties in hypoxia may be divided into three classes: (1) cisplatin and related Pt com-plexes; (2) metal (mamly Pt, Ru, Rh) complexes of nitroaromatic radiosensitizers; (3) complexes of early transition metal scries which may act by electron affinity or thiol depletion.

Most radiosensitization studies have been done with ciinically used plati-num compounds, namely m-diamminedichloroplatinum(II) (cisplatin), carbo-platin and iproplatin. When they are used in conjunction with radiation, they give beneficial results in in vitro and in vivo studies, as wcll as in clinical trials [1, 29, 37, 51], Some other neutral platinum complexes, possessing cis or trans configuration, were shown to be potentiators of radiation induced celi kill. The means by which the platinum complcxes interact with radiation is not elear, but recent studies rule out an electron affinic and thiol depletion mechanisms. One assumes that the radiosensitizing ability of platinum complexes is related to their DNA binding [1, 29, 51]. Platinum compounds are not “truć radiosensitizers” because they do not imply oxygen-mimetic or electron accepting mechanisms. Such compounds are proposed to be named modifiers or potentiators.