Amelioration of Chemotherapy‐Induced Toxicity by Cotreatment with AcSDKP, a Tetrapeptide Inhibitor of Hematopoietic Stem Cell Proliferation

Bogdén, Arthur E.; Carde, Patrice; Paillette, E. Deschamps de; Moreau, Jacques-Pierre; Tubiana, M; Frindel, E

doi:10.1111/j.1749-6632.1991.tb17230.x

Cited by 53 publications

(31 citation statements)

References 6 publications

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“…Thus, one can envisage controlling plasma AcSDKP levels without interfering with blood pressure control. Taking into consideration the important role of AcSDKP in the control of the hematopoietic cycle (11), inhibition of the N-terminal ACE active site may have important clinical applications in facilitating hematopoietic recovery after aggressive cancer chemotherapy (32)(33)(34)(35). The in vivo stability of RXP 407, as well as its pharmacokinetic properties, should allow us to address this issue in the near future.…”

Section: Discussionmentioning

confidence: 99%

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

Dive

Cotton²,

Yiotakis³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

171

186

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The human somatic angiotensin converting enzyme (ACE) contains two homologous domains, each bearing a zinc-dependent active site. All of the synthetic inhibitors of this enzyme used in clinical applications interact with these two active sites to a similar extent. Recently, several lines of evidence have suggested that the N-terminal active site of ACE might be involved in specific hydrolysis of some important physiological substrates, like Acetyl-Seryl-Aspartyl-LysylProline, a negative regulator of hematopoietic stem cell differentiation and proliferation. These findings have stimulated studies aimed at identifying new ACE inhibitors able to block only one of the two active sites of this enzyme. By screening phosphinic peptide libraries, we discovered a phosphinic peptide Ac-Asp-(L) Phe(PO 2 -CH 2 ) (L) Ala-Ala-NH 2 , called RXP 407, which is able to differentiate the two ACE active sites, with a dissociation constant three orders of magnitude lower for the N-domain of the enzyme. The usefulness of a combinatorial chemistry approach to develop new lead structures is underscored by the unusual chemical structure of RXP 407, as compared with classical ACE inhibitors. As a highly potent and selective inhibitor of the N-terminal active site of wild ACE (K i ‫؍‬ 12 nM), RXP 407, which is metabolically stable in vivo, may lead to a new generation of ACE inhibitors able to block in vivo only a subset of the different functions regulated by ACE.

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Section: Discussionmentioning

confidence: 99%

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

Dive

Cotton²,

Yiotakis³

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

171

186

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“…Thus, a myeloprotective agent might be advantageous, allowing dosage and schedule maintenance with a resultant increase in therapeutic activity. In murine in vivo studies, AcSDKP has reduced the myelosuppressive effects of cycle-specific chemotherapy (12,18) or irradiation (19,20). This effect may be a result of the ability of AcSDKP to remove hematopoietic progenitor cells from cell cycle (10).…”

Section: Introduction H Em a Top Oietic Stem A Nd Pr Og En Ito R C Elmentioning

confidence: 95%

Activity of Acetyl-Ser-Asp-Lys-Pro (AcSDKP) on Human Hematopoietic Progenitor Cells in Short-Term and Long-Term Bone Marrow Cultures

Jackson

Özerol

Yan

et al. 2000

Journal of Hematotherapy & Stem Cell Research

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The tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP) is a potent inhibitor of hematopoietic stem cell proliferation. We examined the effects of AcSDKP on the production of granulocyte-macrophage colony-forming cells (CFU-GM) and high proliferative potential colony-forming cells (HPP-CFC) in human long-term bone marrow (LTBM) cultures and CFU-GM and erythroid burst-forming cells (BFU-e) in short-term liquid cultures. The addition of AcSDKP in short-term bone marrow cultures resulted in a maximum depression of the total number of progenitor cells as well as the number of progenitor cells entering cell cycle following culture with 10(-12) to 10(-14) M AcSDKP and 10(-14) M AcSDKP when exogenous cytokines (GM-CSF, IL-3, or SCF) were added. AcSDKP was added daily to LTBM cultures at various concentrations (10(-8) M to 10(-16) M) for up to 5 weeks. In these LTBM culture studies, AcSDKP inhibited the entry of nonadherent progenitor cells into S phase and decreased the number of nonadherent progenitor cells with peak activity at 10(-12) M. In contrast, AcSDKP had no effect on the number of adherent CFU-GM, HPP-CFC, or cellularity per culture or percent of adherent progenitor cells in S phase. These studies indicate that the concentration of the tetrapeptide is critical to the activity of AcSDKP on human hematopoietic progenitor cells. Furthermore, we report that the presence of cytokines or stromal cells also affects the response of progenitor cells to AcSDKP. These results will aid in determining kinetic properties of AcSDKP for the development of clinical protocols to protect normal human hematopoietic stem and progenitor cells following cycle-specific chemotherapy agents.

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“…The dose of AcSDKP ranged from 500 to 0.05 mg/kg/24 h. We have previously shown dose-response characteristics of canine hematopoietic cells comparable to those in other species [14]. Therefore, the final dose used, 0.5 mg/kg/24 h, was based not only on canine data but also on data obtained in murine models by Talmadge et al [26] and Bogden et al (Table 1) [3].…”

Section: Administration Of Acsdkpmentioning

confidence: 96%

“…Hematopoietic stem cells are relatively protected from chemotherapy or irradiation-related toxicity when "quiescent," i.e., arrested in G 0 [3,7,8,12,25]. Thus, agents such as AcSDKP might be useful for stem cell protection in chemo/radiotherapy-treated patients.…”

Section: Introductionmentioning

confidence: 98%

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In vivo radioprotective effect of AcSDKP on canine myelopoiesis

Deeg

Seidel

Hong

et al. 1997

Annals of Hematology

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The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) interferes with G1/S-phase progression, and the resulting cell cycle arrest is thought to protect hematopoietic stem cells against injury by cycle-active cytotoxic agents. We investigated the radioprotective effect of AcSDKP in a canine radiation model. Dogs were given total-body irradiation (TBI) at an exposure rate of 10 cGy/min, either without further therapy (control) or with administration of AcSDKP at 0.05-500 micrograms/ kg/24 h beginning before and continuing until after completion of TBI. At 400 cGy of TBI, one of 28 control dogs and one of eight AcSDKP-treated dogs recovered hematopoiesis (p = 0.40). At 300 cGy, seven of 21 control dogs recovered hematopoiesis compared with five of five AcSDKP-treated dogs (p = 0.01). In dogs given 300 cGy and AcSDKP, the granulocyte nadirs were less profound (p = 0.04) and occurred later (p = 0.04) than among controls; platelet kinetics did not differ. These data suggest, therefore, that AcSDKP provides a radioprotective effect in dogs exposed to 300 cGy TBI. Such an effect might be beneficial in recipients of intensive radiation therapy. Conceivably, the effect on hematopoietic recovery could be amplified by growth factor administration after irradiation.

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Amelioration of Chemotherapy‐Induced Toxicity by Cotreatment with AcSDKP, a Tetrapeptide Inhibitor of Hematopoietic Stem Cell Proliferation

Cited by 53 publications

References 6 publications

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

RXP 407, a phosphinic peptide, is a potent inhibitor of angiotensin I converting enzyme able to differentiate between its two active sites

Activity of Acetyl-Ser-Asp-Lys-Pro (AcSDKP) on Human Hematopoietic Progenitor Cells in Short-Term and Long-Term Bone Marrow Cultures

In vivo radioprotective effect of AcSDKP on canine myelopoiesis

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