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Improving the Chemotherapeutic Index of IUdR Using a Vasoactive Immunoconjugate

We have previously explored the concept of linking monoclonal antibodies (Mabs) to vasoactive or pro-inflammatory peptides for the purpose of enhancing the permeability of blood vessels or increasing blood flow at the tumor site to improve Mab uptake. The primary objective of this 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 xenografts were pretreated with either TNT-1 Mab or the TNT-l/IL2 immunoconjugate. Three hours after pretreatment, the mice were injected with 5-[125-I]iodo-2'-deoxyuridine (125-IUdR) and 1,3, and 6 hours later the mice were sacrificed for biodistribution analysis. Pretreatment with TNT-l/IL-2 led to a 3-fold increase in localization of 125-IUdR in 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 uptake to be achieved. These data suggest that vasoconjugate pretreatment can significantly improve the therapeutic index of chemotherapeutic drugs while decreasing their systemic toxicity.