Rodgers Kathleen, Xiong Shiquin, DiZerega Gere S
University of Southern California, Keck School of Medicine, 1321 N. Mission Road, Los Angeles, CA 90033, USA.
Cancer Chemother Pharmacol. 2003 Feb;51(2):97-106. doi: 10.1007/s00280-002-0509-4. Epub 2002 Dec 19.
Previous studies have shown that angiotensin peptides stimulate the proliferation of hematopoietic progenitors in vitro, promote survival after exposure to lethal irradiation as well as accelerate the recovery of white blood cells (WBC), i.e., lymphocytes, monocytes and neutrophils, and platelets. These changes in the level of formed elements in the blood after irradiation was thought to be due to increases in the numbers of bone marrow progenitors including myeloid, erythroid and megakaryocyte progenitors by the action of angiotensin peptides. In view of these findings, the effect of angiotensin peptides on recovery after chemotherapy was assessed.
The effect of angiotensin II (AII) and angiotensin(1-7) (A1-7) on the recovery of WBC and platelets in the blood, as well as the number of myeloid, erythroid and megakaryocyte progenitors in the bone marrow and the number of myeloid progenitors in the blood after intravenous administration of chemotherapeutic drugs was assessed in a mouse model. RESULTS. In initial studies, subcutaneous administration of 10 or 100 microg/kg per day of AII starting either 2 days before or 2 days after intravenous administration of 5-fluorouracil (5FU) accelerated WBC recovery (return to baseline between 7 and 14 days). Further, consistent with previous observations, the number of myeloid progenitors in the bone marrow and blood was increased after systemic administration of angiotensin peptides. The comparability of A(1-7) and AII in their effect on hematopoietic recovery after chemotherapy was shown in subsequent studies. Daily administration of both AII and A(1-7) increased platelet numbers in the peripheral blood and myeloid, erythroid and megakaryocyte progenitors in the bone marrow. As 5FU is not a stem cell toxin, these studies were repeated with administration of A(1-7) initiated before or after intravenous cyclophosphamide. Following treatment with A(1-7) before cyclophosphamide the numbers of circulating WBC initially increased and then decreased starting on day 14. Following treatment with A(1-7) 2 days after cyclophosphamide the numbers of WBC and the numbers of myeloid progenitors increased in the peripheral blood and bone marrow.
These findings suggest that angiotensin peptides accelerate hematopoietic recovery in multiple cellular lineages after chemotherapy, perhaps through an increase in the number of early hematopoietic progenitors.
先前的研究表明，血管紧张素肽在体外可刺激造血祖细胞增殖，促进致死性照射后的存活，并加速白细胞（即淋巴细胞、单核细胞和中性粒细胞）和血小板的恢复。照射后血液中血细胞成分水平的这些变化被认为是由于血管紧张素肽的作用，包括髓系、红系和巨核细胞祖细胞在内的骨髓祖细胞数量增加所致。鉴于这些发现，评估了血管紧张素肽对化疗后恢复的影响。
在小鼠模型中评估了血管紧张素II（AII）和血管紧张素（1-7）（A1-7）对血液中白细胞和血小板恢复的影响，以及静脉注射化疗药物后骨髓中髓系、红系和巨核细胞祖细胞的数量和血液中髓系祖细胞的数量。结果。在初步研究中，在静脉注射5-氟尿嘧啶（5FU）前2天或后2天开始每天皮下注射10或100μg/kg的AII可加速白细胞恢复（在7至14天内恢复至基线）。此外，与先前的观察结果一致，全身给予血管紧张素肽后，骨髓和血液中髓系祖细胞的数量增加。后续研究显示了A（1-7）和AII在化疗后对造血恢复影响的可比性。每天给予AII和A（1-7）均可增加外周血中的血小板数量以及骨髓中的髓系、红系和巨核细胞祖细胞数量。由于5FU不是干细胞毒素，在静脉注射环磷酰胺之前或之后给予A（1-7）重复了这些研究。在环磷酰胺之前用A（1-7）治疗后，循环白细胞数量最初增加，然后在第14天开始下降。在环磷酰胺后2天用A（1-7）治疗后，外周血和骨髓中的白细胞数量以及髓系祖细胞数量增加。
这些发现表明，血管紧张素肽可能通过增加早期造血祖细胞的数量，加速化疗后多个细胞谱系的造血恢复。
