Tumor resistance and healthy tissue toxicity present major obstacles to the successful use of chemotherapy in the treatment of human cancers. Recent studies suggest that elevated levels of the thiol-rich family of proteins, metallothioneins, protect both malignant and nonmalignant cells from cytotoxic effects of alkylating agents and cDDP. This proposal will evaluate the influence of metallothionein (MT) on the efficacy of cDDP as a chemotherapeutic agent in the treatment of human cancers. Of specific interest are: 1) the relationship between cellular MT levels and tumor resistance to cDDP, and 2) the relationship between cellular MT levels and healthy tissue toxicity. To evaluate the influence of MT on tumor resistance, we propose to measure the cellular expression of MT in two human cancers: transitional cell carcinoma of the urinary bladder and squamous cell carcinoma of the head and neck. Both of these cancers are relatively sensitive to initial therapy with cDDP. To evaluate the influence of MT on healthy tissue toxicity, we will measure cellular levels of MT in the normal bone marrow cells of study patients and in the normal kidney, bone marrow and nerve cells of separate controls. MT levels will be measured on a tissue basis using chromatographic and on a cellular basis using immunofluorescent techniques. Tumor samples will be obtained 1) prior to chemotherapy, 2) after the first cycle of cDDP, and 3) after the completion of a full cycle of treatment or at the time of chemotherapy failure due to toxicity or disease progression. In addition, we plan to determine the growth fraction of a population of cancer cells as a function of measured MT levels, allowing the development of a model which may be used to predict the efficacy of cDDP-related chemotherapy for these cancers. This research will enhance our understanding of the role of MT in cellular drug resistance and healthy tissue toxicity associated with chemotherapeutic agents used in the treatment of human cancers and provide the fundamental data needed to develop rationally designed clinical treatment protocols to exploit modulation of MT in cancer chemotherapy.
| Bahnson, R R; Becich, M; Ernstoff, M S et al. (1994) Absence of immunohistochemical metallothionein staining in bladder tumor specimens predicts response to neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy. J Urol 152:2272-5 |
| Kuo, S M; Kondo, Y; DeFilippo, J M et al. (1994) Subcellular localization of metallothionein IIA in human bladder tumor cells using a novel epitope-specific antiserum. Toxicol Appl Pharmacol 125:104-10 |
| Bahnson, R R; Banner, B F; Ernstoff, M S et al. (1991) Immunohistochemical localization of metallothionein in transitional cell carcinoma of the bladder. J Urol 146:1518-20 |
