2 chlorodeoxyadenosine activity and cross resistance patterns in primary cultures of human hematologic neoplasms

Abstract

2-Chlorodeoxyadenosine (2-CDA) is an adenosine deaminase resistant analogue of deoxyadenosine which has shown clinical activity in human hematologic neoplasms. The exact mode of action of this drug remains the subject of investigation. We applied the Differential Staining Cytotoxicity (DiSC) assay to 50 human tumour specimens obtained from patients with a variety of hematologic malignancies to characterise the activity spectrum of 2-CDA. We evaluated the disease-specific activity of this agent in vitro and compared its relative cytotoxicity with that of other antineoplastic agents in current clinical use. Comparisons were conducted against nitrogen mustard, doxorubicin, vincristine and cytosine arabinoside. Our results indicate that 2-CDA has activity in myeloid and many lymphoid neoplasms but that multiple myeloma specimens reveal significant resistance. Cross resistance studies reveal a correlation between 2-CDA and the alkylator nitrogen mustard but no correlation between 2-CDA and doxorubicin, vincristine nor cytosine arabinoside. The results suggest 2-CDA activity in many human hematologic neoplasms with the clear exception of multiple myeloma and further suggest a relationship between this agent and alkylators of the mustard class. The DiSC assay may provide useful insights in the pre-clinical evaluation of new antineoplastic drugs and may help to elucidate drug activities and mechanisms of action.