RADIOIODODEOXYURIDINE IN CANCER-THERAPY - AN IN-VITRO APPROACH TO DEVELOPING IN-VIVO STRATEGIES

Studies were undertaken to determine the relationship between IUdR con centration and the duration of radiolabeled IUdR treatment required to incorporate the equivalent of a D-0 dose in vitro and to estimate the treatment parameters necessary to incorporate a killing dose in vivo. Methods: W138 (normal human) and Hela (human cancer) cells were grown axenically or in co-culture. The three cultures were treated for 5 da ys with 18.5 kBq/ml [I-125]IUdR. After treatment, the cells were subcu ltured and grown for 7 days in medium without [I-125]IUdR. In separate experiments, Chinese hamster ovary cells (CHO) were labeled with vari ous ratios of radiolabeled (I-125) and nonradiolabeled IUdR and the mo le rate of IUdR incorporation in double-stranded DNA was measured, Mit otically selected CHO cells were incubated without treatment until >98 % were in S phase. At this time, the cells were labeled for 15 min wit h several concentrations of either [I-123]IUdR or [I-125]IUdR and thei r colony survival was measured, Results: After incubation with [I-125] IUdR, selective eradication of Hela cells from a co-culture of W138 an d Hela cells was achieved, The incorporation of IUdR into DNA of CHO c ells, although the sum of a series of enzymatic steps, has the appeara nce of and can be analyzed as a Michaelis-Menton type curve. The maxim um rate of IUdR incorporation (V-max) is 4.424 x 10(-18) mol/min and t he substrate concentration at 1/2 V-max (K) is 3.717 x 10(-6) M IUdR, The D-0 dose rates for [I-123]IUdR and [I-125]IUdR, respectively, are 18.78 and 1.88 initial decays/cell/hr. Conclusion: The D-0 dose for I UdR can be determined from survival curves versus the mole amount of IUdR incorporated in DNA. To be effective as an in vivo treatment it w ill be necessary to manipulate the IUdR delivery time, concentration a nd volume in a manner that assures that the target cells incorporate a cytocidal dose of IUdR.