Previous studies from our laboratory have demonstrated that thyroid hormones 
play a key role in cancer progression. In addition, a deaminated form, 
tetraiodothyroacetic acid (tetrac), that antagonizes the proliferative action of 
these hormones was found to possess anti-cancer functions through its ability to 
inhibit cellular proliferation and angiogenesis. The present study was 
undertaken to investigate whether tetrac could also suppress the development of 
drug resistance, known as a causative factor of disease relapse. Tetrac was 
shown to enhance cellular response in vitro to doxorubicin, etoposide, 
cisplatin, and trichostatin A in resistant tumor cell lines derived from 
neuroblastoma, osteosarcoma, and breast cancer. The mechanism of action of 
tetrac did not involve expression of classical drug resistance genes. However, 
radiolabeled doxorubicin uptake in cells was enhanced by tetrac, suggesting that 
one or more export mechanisms for chemotherapeutic agents are inhibited. Tetrac 
was also found to enhance cellular susceptibility to senescence and apoptosis, 
suggesting that the agent may target multiple drug resistance mechanisms. Tetrac 
has previously been shown to inhibit tumor cell proliferation in vitro. In vivo 
studies reported here revealed that tetrac in a pulsed-dose regimen was 
effective in suppressing the growth of a doxorubicin-resistant human breast 
tumor in the nude mouse. In this paradigm, doxorubicin-sensitivity was not 
restored, indicating that (1) the in vitro restoration of drug sensitivity by 
tetrac may not correlate with in vivo resistance phenomena and (2) tetrac is an 
effective chemotherapeutic agent in doxorubicin-resistant cells.