0145-2126/91 $3.00 + ,00
Leukemia Research Vol. 15, No. 8, p. 766, 1991. Printed in Great Britain.
Pergamon Press plc
LETTER TO THE EDITORS
T H E IMPACT OF L I T H I U M ON H U M A N L E U K E M I C CELLS
THE RECENT report by Becker and Tyobeka [1] prompts us to comment. These authors contend that the difference between their experience and our previously published data [2] indicates that we "probably monitored growth of HL-60s at suboptimal levels" (of lithium). In fact, as expressed in Table 2 of our publication, we employed a much wider range of lithium concentrations than that used by Becker and Tyobeka and this spectrum included that examined by these authors. Furthermore, in comparing our results at the single, identical concentration used in both studies (10 -2 M), we did not observe the enhanced proliferation reported by Becker and Tyobeka. Rather we found a reduction in cell numbers on every day of culture (by comparison with cultures containing no additional lithium). Moreover, at 10 -2 M, lithium substantially reduces normal human granulopoiesis in vitro and is lethal for erythroid progenitors [3]. An alternative explanation for these differences may lie in true biological distinctions between HL60 clones, as suggested by Becker and Tyobeka. Such distinctions were alluded to (on page 295) in our report. It would have been of interest to know whether the pronounced reduction in cell numbers, observed to follow proliferation of HL-60 enhanced by lithium, was accompanied by morphological or other evidence of differentiation (that would lead to inevitable cell death) so avoiding the need to postulate opposing actions of the same concentration of lithium on the same cells. In our own studies no such evidence was seen. These comments notwithstanding, experiments performed in vitro, with concentrations of lithium of I>2.5× 10-3M (as employed by Becker and
Tyobeka), are of limited clinical relevance. As these authors have stated correctly, such levels are predictably associated with toxicity in vivo, which is mirrored in vitro by reduced clonogenesis of all lineages studied in normal human bone marrow [3]. It was for this reason, and the prospect that administration of lithium may have a beneficial effect for patients with leukemia, that we focused our detailed studies on the effects of "therapeutic" concentrations. At 3 × 10 -4 M lithium stimulated expression of c-myc and c-fins, as judged by Northern-blot analysis [2]. If Becker and Tyobeka have conducted experiments at similar concentrations, the results may be of further interest.
REFERENCES Becker R. W. & Tyobeka E. M. (1990) Lithium
enhances the proliferation of HL-60 promyelocytic leukemia cells. Leukemia Res. 14, 879. 2. Knight S. C., Harnish D., Scheid E., Koekebakker M. & Barr R. D. (1989). Lithium and hydrocortisone interactions on cell growth and gene expression in human promyelocytic leukemia (HL-60). Leukemia Res. 13, 289. 3. Barr R. D., Koekebakker M., Brown E. A. & Falbo M. C. (1987). Putative role for lithium in human hematopoiesis. J. Lab. clin. Med. 109, 159. RONALD D. BARR* DELSWORTH HARNISHt
Departments of *Pediatrics and tPathology McMaster University Hamilton Ontario Canada L8N 3Z5
766
Leukemia Research Vol. 15, No. 8, p. 766, 1991. Printed in Great Britain.
Pergamon Press plc
LETTER TO THE EDITORS
T H E IMPACT OF L I T H I U M ON H U M A N L E U K E M I C CELLS
THE RECENT report by Becker and Tyobeka [1] prompts us to comment. These authors contend that the difference between their experience and our previously published data [2] indicates that we "probably monitored growth of HL-60s at suboptimal levels" (of lithium). In fact, as expressed in Table 2 of our publication, we employed a much wider range of lithium concentrations than that used by Becker and Tyobeka and this spectrum included that examined by these authors. Furthermore, in comparing our results at the single, identical concentration used in both studies (10 -2 M), we did not observe the enhanced proliferation reported by Becker and Tyobeka. Rather we found a reduction in cell numbers on every day of culture (by comparison with cultures containing no additional lithium). Moreover, at 10 -2 M, lithium substantially reduces normal human granulopoiesis in vitro and is lethal for erythroid progenitors [3]. An alternative explanation for these differences may lie in true biological distinctions between HL60 clones, as suggested by Becker and Tyobeka. Such distinctions were alluded to (on page 295) in our report. It would have been of interest to know whether the pronounced reduction in cell numbers, observed to follow proliferation of HL-60 enhanced by lithium, was accompanied by morphological or other evidence of differentiation (that would lead to inevitable cell death) so avoiding the need to postulate opposing actions of the same concentration of lithium on the same cells. In our own studies no such evidence was seen. These comments notwithstanding, experiments performed in vitro, with concentrations of lithium of I>2.5× 10-3M (as employed by Becker and
Tyobeka), are of limited clinical relevance. As these authors have stated correctly, such levels are predictably associated with toxicity in vivo, which is mirrored in vitro by reduced clonogenesis of all lineages studied in normal human bone marrow [3]. It was for this reason, and the prospect that administration of lithium may have a beneficial effect for patients with leukemia, that we focused our detailed studies on the effects of "therapeutic" concentrations. At 3 × 10 -4 M lithium stimulated expression of c-myc and c-fins, as judged by Northern-blot analysis [2]. If Becker and Tyobeka have conducted experiments at similar concentrations, the results may be of further interest.
REFERENCES Becker R. W. & Tyobeka E. M. (1990) Lithium
enhances the proliferation of HL-60 promyelocytic leukemia cells. Leukemia Res. 14, 879. 2. Knight S. C., Harnish D., Scheid E., Koekebakker M. & Barr R. D. (1989). Lithium and hydrocortisone interactions on cell growth and gene expression in human promyelocytic leukemia (HL-60). Leukemia Res. 13, 289. 3. Barr R. D., Koekebakker M., Brown E. A. & Falbo M. C. (1987). Putative role for lithium in human hematopoiesis. J. Lab. clin. Med. 109, 159. RONALD D. BARR* DELSWORTH HARNISHt
Departments of *Pediatrics and tPathology McMaster University Hamilton Ontario Canada L8N 3Z5
766
