Radiation and Platinum Drug Interaction

Abstract

Platinum drugs have chemical as well as biochemical and biological effects on cells, all of which may interact with radiation effects. They inhibit recovery from sublethal and potentially lethal radiation damage. They produce a pattern of chromosome aberrations analogous to that from alkylating agents. Cellular sensitivity to platinum is increased when glutathione levels are reduced, just as is radiosensitivity. There is a pattern of drug sensitivity throughout the phases of the cell cycle which is different from that for radiosensitivity. The ideal platinum drug-radiation interaction would achieve radiosensitization of hypoxic tumour cells with the use of a dose of drug which is completely non-toxic to normal tissues. Electron-affinic agents are employed with this aim, but the commoner platinum drugs are only weakly electron-affinic. They do have a quasi-alkylating action however, and this DNA targeting may account for the radiosensitizing effect which occurs with both pre- and post-radiation treatments. Because toxic drug dosage is usually required for this, the evidence of the biological responses to the drug and to the radiation, as well as to the combination, requires critical analysis before any claim of true enhancement, rather than simple additivity, can be accepted. The amount of enhancement will vary with both the platinum drug dose and the time interval between drug administration and radiation. Clinical schedules may produce an increase in tumour response and/or morbidity, depending upon such dose and time relationships.

The Effects of Carbocisplatin and Radiation on Skin Flap Survival

“…Cell cycle perturbations and reac¬ tions with nonprotein SH groups also occur with platinum radiosensitization. 47 Sublethal damage occurs with single-strand breaks that are repaired with DNA excision repair and after replica¬ tion repair processes.56"58 The gaps filled in by the replica¬ tion repair process may occur by recombination, de novo synthesis,59 or by passing the lesion via branch migra¬ tions.60 Postradiation cellular damage occurs by the inhi¬ bition of such recovery processes. Usually the repair of DNA single-stranded breaks are rapid with about 85% complete at 60 minutes after irradiation.17 Studies have shown the DNA repair processes after treatment with cisplatin to be significantly slower.61 Steric hinderance of platinum-bound DNA leads to misrepaired radiation lesions resulting in chromatid aberrations, possibly in a supra-additive manner.…”

“…Usually the repair of DNA single-stranded breaks are rapid with about 85% complete at 60 minutes after irradiation.17 Studies have shown the DNA repair processes after treatment with cisplatin to be significantly slower.61 Steric hinderance of platinum-bound DNA leads to misrepaired radiation lesions resulting in chromatid aberrations, possibly in a supra-additive manner. 47 Of the 93 animals entered into this study, 71 (76%) sur¬ vived through the completion of the experiment on day 63. Anesthetic deaths occurred in eight (8.6%), while loss of the remaining 14 (14.4%) animals was attributed to any combination of stress and toxicity from surgery, radiation, or carbocisplatin.…”

Radiation and Platinum Drug Interaction

“…50, NO. 5, 945-946 Letter to the Editor Radiation and platinum drug interaction (Received 4 June 1986) In a review article entitled 'Radiation and platinum drug interaction' by Nias (1985), we were more than somewhat surprised to read an inaccurate citation of the details and misrepresentation of the significance of a case reported by us (Golding and van Zanten 1983).…”

Mitozolomide-induced sensitisation of mammalian cells in vitro to radiation

“…Radiation can enhance interstrand cross-linking by BCNU (Tofilon et al, 1984). Cross-linking agents have also been found to enhance radiation-induced cell killing in mammalian cells in vitro (Nias, 1985;Wheeler et al, 1977) and the combination can be more effective in vivo than the single agents (Barker et al, 1979;Walker & Gehan, 1976).…”