Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
DIDEOXYNUCLEOSIDES AS SPECIFIC ANTILEUKEMIC AGENTS IN LYMPHOBLASTIC DISEASE (MEETING ABSTRACT)
Fifteenth Symposium of the International Association for Comparative Research on Leukemia and Related Disease. October 6-11, 1991, Padova/Venice, Italy, p. 55, 1991.. Unique Identifier : AIDSLINE ICDB/92682405 McCaffrey RP; Torres ER; Cronin K; Safran H; Dhawan R; Boston Univ. Medical Center, Boston, MA
Abstract:
Intense interest is now focused on the biological activity of 2',3'-dideoxynucleosides (ddNs) since their introduction as antiretroviral agents in HIV-infected individuals. We have noted that the lymphoblastic leukemia-associated DNA polymerase, terminal deoxynucleotidyl transferase (TdT), like HIV reverse transcriptase, recognizes ddNTPs as substrate analogs and makes chain-terminating ddNMP additions to nascent DNA. To explore the biologic significance of this, we exposed a series of TdT-positive and TdT-negative cell lines to 2',3'-dideoxyadenosine (ddA) as a representative ddN. Intracellular anabolic conversion of ddA to ddATP was augmented by the addition of noncytotoxic conformycin to inhibit ADA. All 7 TdT-positive cell lines were damaged at 48 hr (85-95% cell death), whereas 5 TdT-negative cell lines were unaffected (0-15% cell death). Freshly harvested TdT-positive ALL cells from 8 patients were likewise killed by ddA ex vivo, whereas cells from 6 patients with TdT-negative acute leukemia were unaffected. Experiments with a murine cell line, converted from a TdT-negative to a TdT-positive status by transfection with a TdT cDNA, suggest that TdT per se plays a central role in the observed ddA cytotoxicity; the TdT-negative parental line was ddA insensitive, whereas after conversion to a TdT-positive state, there was 90% cell death following ddA exposure. The concentrations of ddA required for cell death exceed what would be clinically achievable. Hence, we have sought ddA derivatives with enhanced cytotoxic potential. To date the most promising agent has been a halogenated derivative, 2-chloro-ddA. Augmented cytotoxicity in TdT-positive cells is most likely due to its lack of recognition by ADA (Ki greater than 500 uM). When given as a 5-day course to BALB/c mice, the most prominent effect of 2-chloro-ddA is transient thymic atrophy. In an ongoing study of a murine TdT-positive diffuse lymphoblastic lymphoma disease model in BALB/c mice, a 3-day course of 2-chloro-ddA results in a dramatic decrease in tumor burden when assessed on day 28 post-therapy. A comprehensive dose-finding study in this murine model is now in progress. The synthesis of additional 2-substituted ddA derivatives is expected to uncover more agents with cytotoxic specificity for TdT-positive cells.
Keywords: Dideoxyadenosine/*PHARMACOLOGY/*THERAPEUTIC USE Human Leukemia, Lymphocytic, Acute/*DRUG THERAPY ABSTRACT 920830
M9281101
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
