ter-199 and Neoplasms

The use of cytotoxic chemotherapy for cancer therapy has been very successful in the treatment and often cure of patients with particular neoplasms, such as testicular carcinomas and some lymphomas. In addition, the use of adjuvant chemotherapy in patients whose primary tumor has been surgically removed contributes significantly to cure rates in some of the more common malignancies such as breast carcinoma and colon cancer. Nonetheless, for most patients with metastatic malignancies, current antineoplastic drugs provide only brief remissions with few or no long term cures. In addition, the side effects of therapy lead to substantial morbidity in nearly all patients. Insights derived from model system studies on two glutathione based lead compounds, TER286 and TER199, suggest new clinical strategies and raise interesting basic research questions regarding the cell biology foundations of cancer chemotherapy.

Topics: Animals; Antineoplastic Agents; Biotransformation; Cytotoxins; Drug Resistance; Enzyme Inhibitors; Female; Glutathione; Glutathione Transferase; Hematopoiesis; Humans; Male; Neoplasms

Glutathione S-transferase P (GSTP) is a component of a complex series of pathways that provide cellular redox homeostasis. It is an abundant protein in certain tumors and is over-expressed in cancer drug resistance. It has diverse cellular functions that include, thiolase activities with small electrophilic agents or susceptible cysteine residues on the protein to mediate S-glutathionylation, and chaperone binding with select protein kinases. Preclinical and clinical testing of a nanomolar inhibitor of GSTP, TLK199 (Telintra; Ezatiostat) has indicated a role for the enzyme in hematopoiesis and utility for the drug in the treatment of patients with myelodysplastic syndrome.

Topics: Glutathione; Glutathione Transferase; Humans; Neoplasms; Protein Binding