Action of deoxycoformycin on human T cell colonies in vitro.
The potent adenosine deaminase inhibitor, deoxycoformycin (dCF), is currently under evaluation in the treatment of lymphoid malignancy. We show that dCF inhibits the growth in soft agar of T cell colonies from PHA stimulated human peripheral blood lymphocytes. In contrast to previous attempts to develop an in vitro model for analysis of the drug's action, concentrations lower than 10(-9)M are effective, and no 'priming' by pharmacological concentrations of adenosine is required. Maximum inhibition is obtained when dCF is present over the first 4 hr of cellular exposure to PHA. T cells already proliferating in response to PHA are less sensitive to dCF, implying that S-phase events are not primary targets of the drug's action. Colony inhibition does not appear to be due to alteration in the production of, or sensitivity to, soluble T cell growth factors. In suspension cultures, dCF at concentrations up to 10(-5)M fails to inhibit early PHA-induced volume changes, or later mitosis, in peripheral blood lymphocytes. The results show that there is a critical dCF sensitive step early in PHA stimulation. It involves those T cells capable of forming colonies and may be conditioned by the cellular microenvironment.
D000328:Adult; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002999:Clone Cells / Q000187:drug effects; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology*; D003470:Culture Media; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D015649:Pentostatin; D010835:Phytohemagglutinins / Q000494:pharmacology; D012263:Ribonucleosides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors
D003470:Culture Media; D007376:Interleukin-2; D010835:Phytohemagglutinins; D012263:Ribonucleosides; D003070:Coformycin; D015649:Pentostatin