Adenosine deaminase (ADA), an enzyme important in purine nucleoside metabolism, is essential for cell differentiation and proliferation. Pharmacologic inhibition of this enzyme by deoxycoformycin (dCF) has been explored for its chemotherapeutic potential in lymphoproliferative malignancy. Objective responses to dCF have been observed in patients with advanced chronic lymphocytic leukemia (CLL) and cutaneous T-cell lymphoma (CTCL) at doses which are nontoxic. The proposed mechanism of dCF induced tumor cell cytotoxicity directly involves the intracellular accumulation of both deoxyadenosine (dAdo) and dATP. The increase in dATP inhibits ribonucleotide reductase with consequent impairment in DNA synthesis. The increase in dAdo will inhibit S-adenosylhomocysteine hydrolase (SAHH) activity and potentially will interfere with important intracellular methylation reactions. This study will focus on a determination of the known biochemical parameters that are important to achieve and maintain an intracellular pool of dATP in the neoplastic cells from patients with either advanced CLL or CTCL. Neoplastic cells isolated from the peripheral blood, palpable lymph nodes, or skin tumors will be characterized by both standard surface markers and monoclonal antibodies before treatment to define the percentage of neoplastic cells present in the patient sample. The specific activity of the following enzymes will be determined by radiochemical assay in the neoplastic cells: ADA, deoxyadenosine kinase, cytoplasmic 5' nucleotidase, and SAHH before and after treatment. Intracellular deoxyribonucleotides and ribonucleotides will be quantitated by DNA polymerase and high performance liquid chromatography methods before and after dCF administration. A correlation of these specific biochemical parameters with the observed clinical response will be accomplished. Patients will have a baseline determination of the rate of radiolabelled dCF transport into the neoplastic cells. An effort will be made to define the mechanism of drug resistance in the non-responsing or relapsed patients. In patients with resistant disease, neoplastic cells will be procured to again measure the rate of dCF intracellular transport, to determine the specific activity of ADA in the resistant cells, and to quantitate the Km for ADA in the resistant cells using both dADO and adenosine as substrates. This study will define the utility of a biochemical predictive model for testing drug sensitivity in patients with lymphoid malignancies.
| Leiby, J M; Grever, M R; Staubus, A E et al. (1988) Phase I clinical investigation of fludarabine phosphate by a loading-dose and continuous-infusion schedule. J Natl Cancer Inst 80:447-9 |
| Leiby, J M; Snider, K M; Kraut, E H et al. (1987) Phase II trial of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-monophosphate in non-Hodgkin's lymphoma: prospective comparison of response with deoxycytidine kinase activity. Cancer Res 47:2719-22 |
