The effect of combined treatment with a platinum complex and ionizing radiation on chinese hamster ovary cells in vitro

Abstract

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

Isobologram analysis of the combined effects of anti-tumour platinum complexes and ionizing radiation on mammalian cells

“…3). Time and dose relationships with combined cis-PAD and y-ray treatment The experiments described in this section were reported briefly by Szumiel & Nias (1976b) in terms of DMF values only. The full cis-PAD and y-ray dose-survival curves for these cells are presented in Fig.…”

“…This alteration was clearly seen when radiation survival data obtained for drug-pretreated cells were normalized to survival for drug-treated, unirradiated cells and plotted against radiation dose. The resulting survival curves had both a smaller shoulder and a lower slope than those for drug-untreated cells, when adequate drug concentration and timing were applied (Szumiel & Nias, 1976b).…”

“…WE PREVIOUSLY REPORTED that pretreatment with cis platinum complexes PAD [cis-dichlorobis (cyclopentylamine) platinum (II)] and CHIP (cis-dichlorobis (isopropylamine) trans-dihydroxy platinum (IV)] alters the slope of the X-ray dose-survival curve for CHO (Chinese hamster ovary) cells (Szumiel & Nias, 1976b;Nias & Szumiel, 1977). This alteration was clearly seen when radiation survival data obtained for drug-pretreated cells were normalized to survival for drug-treated, unirradiated cells and plotted against radiation dose.…”

“…Fig. 1 Steel & Peckham (1979) and, (B) the way of estimating the results of combined treatment with 2 agents as applied in our previous papers (Szumiel & Nias, 1976b;Nias & Szumiel, 1977).…”

Combination studies with misonidazole and a cis-platinum complex: cytotoxicity and radiosensitization in vitro

“…5) appear parallel, which suggests that the two compounds show a degree of additivity that cannot be explained if they sensitize wholly by the same mechanism(s). DISCUSSION cis-Platinum complexes can increase the radiation sensitivity of cells in vitro under both aerobic and hypoxic conditions (Richmond & Powers, 1976;Szumiel & Nias, 1976;Nias & Szumiel, 1977;Richmond et al, 1977;Douple & Richmond, 1978) with the greatest effect apparently on the hypoxic cells (Richmond & Powers, 1976;Richmond et al, 1977;Douple & Richmond, 1978;Nias et al, 1979). In the present work 5tM cis-Pt(II) increases the radiation sensitivity of hypoxic mammalian cells, giving an ER of 1-12.…”