Morphological Alterations in Blood and Bone Marrow of Ribavirin-Treated Monkeys

Cosgriff, Thomas M.; Hodgson, Loreen A.; Canonico, Peter G.; White, Jeff; Kastello, Michael D.; Donovan, Janet; Ross, Paul E.

doi:10.1159/000206386

Cited by 22 publications

(11 citation statements)

References 9 publications

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“…These were the nucleoside analogs TF and RV (Knight et al, 1987;Srivastava et al, 1977;Weber et al, 1988;Witkowski et al, 1972). RV has been used clinically as an antiviral, and an increase in platelet numbers has been reported in primate and human subjects given this compound (Cosgriff et al, 1984;Shulman, 1984). Consequently we focused our attention on the effects of this agent, alone, and in combination with cytokines as described below.…”

Section: Resultsmentioning

confidence: 99%

“…They have been shown to act as differentiation agents in such well known cell lines as K562 and HL-60 (Goldstein et al, 1991;Kharbanda et al, 1988;Yu et al, 1989), as well as in primary cell culture (Wright et al, 1992) and it has been suggested that they function by interfering with the activity of G protein linked signal- ling systems (Wright, 1987). RV has also received application in the clinic as an antiviral agent (Witkowski et al, 1972) and has been reported to increase megakaryocyte and platelet levels in primates including humans (Cosgriff et al, 1984;Shulman, 1984). Consistent with the literature we have found that CMK cells treated with RV showed reduced GTP levels relative t o control cells (unpublished data).…”

Section: Discussionmentioning

confidence: 99%

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IL‐3 and ribavirin induce high level expression of megakaryocytic markers and messages during long‐term treatment of a megakaryocytic leukemia cell line

Majumdar

Kerby

Mullikin

et al. 1994

Journal Cellular Physiology

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Megakaryocyte differentiation is a lengthy process with cells moving through a continuum delineated by the sequential expression of specific gene products. The limited number of primary cells available from marrow for analysis has brought attention to some leukemic cell lines which show enhanced megakaryocyte marker expression following incubation with inducing agents, the most common of which is phorbol myristate acetate (PMA). We developed an alternative induction protocol for the megakaryocytic leukemic cell line CMK, which involved incubation of the cells with IL-3 and the nucleoside analog, ribavirin, for 1-2 weeks. This treatment was neither toxic nor cytostatic and yielded increased levels of the surface glycoproteins GPIIb/IIIA and GPIb-IX. Levels of some megakaryocytic messages (GPIIIa, GPIX) showed a marked rise by 12 days of incubation in the inducer combination. This was due to a synergistic interaction between IL-3 and ribavirin which influenced both transcriptional and posttranscriptional events. Light and electron microscopy demonstrated the presence of large polyploid cells, with morphological features similar to those of megakaryocytes, in the induced cultures. Analysis of the heterogeneity of response in the cell population to the induction regimen after several days of treatment suggested that cells which failed to display surface markers had been stimulated by the inducers but did not have sufficient time to complete expression of that marker. The results were consistent with the view that the cells in the starting population were distributed along a temporal expression pathway, and those which were first to express the earliest marker would also lead in the expression of a later marker. The order of expression was the same as that during normal megakaryocyte development.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IL‐3 and ribavirin induce high level expression of megakaryocytic markers and messages during long‐term treatment of a megakaryocytic leukemia cell line

Majumdar

Kerby

Mullikin

et al. 1994

Journal Cellular Physiology

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“…Therefore it has been proposed that anemia during treatment with RBV/IFN is a "mixed" form of anemia, with extravascular hemolysis plus concomitant bone marrow suppression. Although data from animal studies showed some suppressive effect of RBV on erythrocyte production, this has never been confirmed in humans under therapeutic doses [46,47]. However, even during monotherapy with IFN for the treatment of HCV infection mild anemia was observed, and this was not accompanied by compensatory reticulocytosis [14,15,39].…”

Section: Risk Factors For Ribavirin-induced Anemiamentioning

confidence: 99%

Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research

Russmann

Grattagliano²,

Portincasa³

et al. 2006

CMC

126

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Ribavirin (RBV) is an antiviral nucleoside analogue commonly used in combination with interferon for the treatment of chronic hepatitis C. Severe anemia develops in about 10% of treated patients, and requires close monitoring of hemoglobin and often RBV dose reduction, which may compromise sustained virologic response. Anemia is likely related to extensive RBV accumulation in erythrocytes subsequent to active unidirectional transmembraneous transport. RBV exerts its toxicity through an inhibition of intracellular energy metabolism and oxidative membrane damage, leading to an accelerated extravascular hemolysis by the reticulo-endothelial system. Concentration-dependent toxicity and improvement of anemia upon dose-reduction point towards the importance of pharmacokinetic factors for RBV-induced anemia. On the other hand, pronounced variability in the correlation between RBV concentration and Hb reduction limits the prediction of anemia based on plasma or erythrocyte concentrations in individual patients and points towards additional factors determining individual susceptibility to RBV-induced anemia. Recent studies suggest that erythrocyte oxidative defense mechanisms may play an important role in RBV-induced anemia. Clinical risk factors for severe RBV-induced anemia include impaired renal function, high age, high dose per body weight and female gender. Determination of RBV concentrations has little value in the management of anemia. The only proven effective prevention of RBV-induced anemia is the concomitant administration of erythropoietin. Future research on RBV pharmacokinetics and pharmacodynamics, as well as erythrocyte antioxidant defense mechanisms may improve safety and efficacy of RBV therapy and guide the development of new treatments for RBV-induced anemia and alternative antiviral agents.

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“…The CMK cell system described here should permit analysis of the activity of a natural factor, IL-3, on the aspects of early and midphase megakaryocytic development which appear to be recapitulated by this system. While RV is not a physiological factor it should be noted that it does stimulate megakaryocyte and platelet levels in primates and humans when administered clinically (Cosgriff et al, 1984;Shulman, 1984). Its activity displayed in this system may be reflective of its activity in vivo.…”

Section: Discussionmentioning

confidence: 99%

IL‐3 and ribavirin induce differentiation and growth suppression during long‐term treatment of a megakaryocytic leukemia cell line

Majumdar

Kerby

Mullikin

et al. 1995

Journal Cellular Physiology

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Differentiation of the megakaryocytic leukemia cells, CMK, was induced by long-term (12 day) treatment with the combination of IL-3 and the nucleoside analogue ribavirin (RV), which reduces cellular GTP levels. In a previous report we demonstrated the induction of early messages and antigens, as well as the formation of giant polyploid cells in the cultures (Majumdar et al., 1994, J. Cell. Physiol., 160:29-39). Here we show high level induction of messages for the late markers, Platelet Factor 4, GMP140 (P-Selectin), thrombospondin, and beta thromboglobulin. The induced cells are also positive for these antigens by immunocytochemical analysis. The high level message induction resulted from synergy between the inducers. Pretreatment of the cells with IL-3 could accelerate the rise in message seen with the inducer combination. The increase in differentiation markers was accompanied by a reduction of the proliferative capacity of the cells. Riboguanosine, which has anti differentiation activity, blocked the induction of early and late antigens by the inducer combination, and also by IL-3 acting alone, but did not block the reduction in proliferative competence. In this model of megakaryocytic differentiation IL-3 treatment yields an initial stimulation of growth followed by growth suppression, and is the principal driver of the differentiation process. RV functions primarily as a stimulator of message and protein expression in synergy with IL-3.

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Morphological Alterations in Blood and Bone Marrow of Ribavirin-Treated Monkeys

Cited by 22 publications

References 9 publications

IL‐3 and ribavirin induce high level expression of megakaryocytic markers and messages during long‐term treatment of a megakaryocytic leukemia cell line

IL‐3 and ribavirin induce high level expression of megakaryocytic markers and messages during long‐term treatment of a megakaryocytic leukemia cell line

Ribavirin-Induced Anemia: Mechanisms, Risk Factors and Related Targets for Future Research

IL‐3 and ribavirin induce differentiation and growth suppression during long‐term treatment of a megakaryocytic leukemia cell line

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