IMPROVING THE CHEMOTHERAPEUTIC INDEX OF IUDR USING A VASOACTIVE IMMUNOCONJUGATE

We have previously explored the concept of linking monoclonal antibodi es (Mabs) to vasoactive or pro-inflammatory peptides for the purpose o f enhancing the permeability of blood vessels or increasing blood flow at the tumor site to improve Mab uptake. The primary objective of thi s study was to determine if this approach could be used to improve the therapeutic index of smaller drugs, such as chemotherapeutic agents. For these studies, nude mice bearing ME-180 human cervical carcinoma x enografts were pretreated with either TNT-1 Mab or the TNT-1/IL-2 immu noconjugate. Three hours after pretreatment, the mice were injected wi th 5-[125-I]iodo-2'-deoxyuridine (125-IUdR) and 1, 3, and 6 hours late r the mice were sacrificed for biodistribution analysis. Pretreatment with TNT-1/IL-2 led to a 3-fold increase in localization of 125-IUdR i n the tumor at all three time points compared to pretreatment with TNT -1 alone. In addition, there was no increase in the amount of drug in normal tissues, which enabled high tumor:normal organ ratios of drug u ptake to be achieved. These data suggest that vasoconjugate pretreatme nt can significantly improve the therapeutic index of chemotherapeutic drugs while decreasing their systemic toxicity.