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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.

Using a clonogenic assay in vitro, it has been shown that exposure to azelaic acid (1-100 mM) for 24 hours has a dose-dependent effect on the survival of the colony-forming ability of murine (B16) and human (HMB2, and SK23) melanoma cells as compared with a non-melanotic non-tumoral Chinese hamster cell line (CHO). Both human cell lines were more sensitive to the diacid than the murine cells, and the HMB2 cells were more sensitive than the SK23 cells. These differences may be partly correlated with differences in pigmentation and doubling times between the three melanoma cell lines. The two human lines were more pigmented than the B16, and the SK23 more than the HMB2; the human lines had a longer doubling time than the others.

Summary.-Cis-dichlorobis(cyclopentylamine)platinum II (DBCP) belongs to the group of platinum complexes which have recently been reported to have anti-tumour activity. Its cytotoxic activity in CHO cells is not cell-age-dependent, but enhancement of the effect of ionizing radiation is both dose-and cell cycle phase-dependent. In asynchronous cell populations DBCP acts as a dose-modifying factor for ionizing radiation. Doses of DBCP reducing survival of CHO cells to 26% and 4% applied 1 h before irradiation reduce the Do value of radiation dose-survival curves by factors of 1-34 and 1 59 respectively.In synchronized CHO populations enhancement by DBCP of the effect of radiation is most pronounced in G1 and in late S while it is reduced in mid-S. Possible mechanisms of DBCP-radiation interaction are discussed. PLATINUM complexes were reported by Rosenberg et al. (1969) to have antibiotic and antitumour activities. Several years later one of the simplest inorganic Pt complexes, cis-dichlorodiammine platinum (II) (cis-DDP) has been reported to be effective in the treatment of some human cancers (e.g. Rossof, Slayton and Perlia, 1972;Wallace and Digby, 1974;Wiltshaw and Carr, 1974). In 1972, Connors et al. synthesized a series of organic platinum complexes, some of which had significantly higher therapeutic indices than cis-DDP with a plasma-cell tumour in mice.One of these is cis-dichlorobis(cyclopentylamine)platinum (II), or DBCP. The structure of this coordination complex is shown in Fig. 1

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