Comte L, Lorgeot V, Bignon J, Volkov L, Dupuis F, Wdzieczak-Bakala J, Praloran V
Laboratoire d'Hématologie Expérimentale, Limoges, France.
Eur J Clin Invest. 1998 Oct;28(10):856-63. doi: 10.1046/j.1365-2362.1998.00356.x.
The tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP), a physiological inhibitor of the proliferation of haematopoietic stem cells, is degraded by the angiotensin-I-converting enzyme (ACE). Whereas synthetic AcSDKP (Goralatide) protects normal mice from the haematological toxicity of chemotherapy, it has a lower beneficial effect in humans. This discrepancy could be dependent on Goralatide administration schedules, as well as on the endogenous concentrations of AcSDKP and ACE, which vary during chemotherapy.
We investigated the effect of one myelotoxic dose of 5-fluorouracil (5-FU, 200 mg kg-1) administered without or with Goralatide on blood, bone marrow (BM) and spleen AcSDKP concentrations, ACE activity, nucleated cell counts and survival of the primitive haematopoietic progenitors high proliferative potential colony-forming cells (HPP-CFCs).
The 5-FU treatment dramatically decreased the BM concentrations of AcSDKP by 73% and increased the ACE activity in plasma by 50% during the period of active BM regeneration. Repeated injections of Goralatide from 24 h before to 36 h after the i.p. injection of 5-FU spared BM HPP-CFCs. As an injection of 10 mg of Goralatide induced a short peak of plasma AcSDKP without modifying its BM concentrations, we suggest that its protective effect on HPP-CFCs could be mediated by its interference with other plasma molecules targeting to the BM.
By improving our knowledge of the biology of AcSDKP in vivo during chemotherapy, our results could help to better define the therapeutic use of Goralatide.
四肽乙酰 - 丝氨酸 - 天冬氨酸 - 赖氨酸 - 脯氨酸（AcSDKP）是造血干细胞增殖的生理抑制剂，可被血管紧张素转换酶（ACE）降解。虽然合成的AcSDKP（戈拉替德）可保护正常小鼠免受化疗的血液学毒性，但在人类中的有益作用较低。这种差异可能取决于戈拉替德的给药方案，以及化疗期间AcSDKP和ACE的内源性浓度变化。
我们研究了单剂量骨髓毒性药物5 - 氟尿嘧啶（5 - FU，200 mg/kg）在不使用或使用戈拉替德的情况下，对血液、骨髓（BM）和脾脏中AcSDKP浓度、ACE活性、有核细胞计数以及原始造血祖细胞高增殖潜能集落形成细胞（HPP - CFCs）存活的影响。
在活跃的骨髓再生期间，5 - FU治疗使BM中AcSDKP浓度显著降低73%，并使血浆中ACE活性增加50%。从腹腔注射5 - FU前24小时至注射后36小时重复注射戈拉替德可使BM中的HPP - CFCs免受损伤。由于注射10 mg戈拉替德会诱导血浆AcSDKP出现短暂峰值，而不改变其BM浓度，我们认为其对HPP - CFCs的保护作用可能是通过干扰其他靶向BM的血浆分子介导的。
通过增进我们对化疗期间体内AcSDKP生物学特性的了解，我们的结果有助于更好地确定戈拉替德的治疗用途。
