Radioiododeoxyuridine in cancer therapy: an in vitro approach to developing in vivo strategies.

Abstract

Studies were undertaken to determine the relationship between IUdR concentration and the duration of radiolabeled IUdR treatment required to incorporate the equivalent of a D(o) dose in vitro and to estimate the treatment parameters necessary to incorporate a killing dose in vivo. W138 (normal human) and HeLa (human cancer) cells were grown axenically or in co-culture. The three cultures were treated for 5 days with 18.5 kBq/ml [125I]IUdR. After treatment, the cells were subcultured and grown for 7 days in medium without [125I]IUdR. In separate experiments, Chinese hamster ovary cells (CHO) were labeled with various ratios of radiolabeled (125I) and nonradiolabeled IUdR and the mole rate of IUdR incorporation in double-stranded DNA was measured. Mitotically selected CHO cells were incubated without treatment until > 98% were in S phase. At this time, the cells were labeled for 15 min with several concentrations of either [123I]IUdR or [125I]IUdR and their colony survival was measured. After incubation with [125I]IUdR, selective eradication of HeLa cells from a co-culture of W138 and HeLa cells was achieved. The incorporation of IUdR into DNA of CHO cells, although the sum of a series of enzymatic steps, has the appearance of and can be analyzed as a Michaelis-Menton type curve. The maximum rate of IUdR incorporation (Vmax) is 4.424 x 10(-18) mol/min and the substrate concentration at 1/2 Vmax (K) is 3.717 x 10(-6) M IUdR. The Do dose rates for [123I]IUdR and [125I]IUdR, respectively, are 18.78 and 1.88 initial decays/cell/hr. The D(o) dose for *IUdR can be determined from survival curves versus the mole amount of *IUdR incorporated in DNA. To be effective as an in vivo treatment it will be necessary to manipulate the IUdR delivery time, concentration and volume in a manner that assures that the target cells incorporate a cytocidal dose of *IUdR.