Alisauskas R M, Goldenberg D M, Sharkey R M, Blumenthal R D
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA.
Int J Cancer. 1997 Jan 27;70(3):323-9. doi: 10.1002/(sici)1097-0215(19970127)70:3<323::aid-ijc13>3.0.co;2-g.
The hemoregulatory peptide, pGlu-Glu-Asp-Cys-Lys (pEEDCK or HP5b), has been shown to reversibly inhibit the proliferation of bone-marrow progenitor cells, and has been reported to protect mice from the myelotoxicity associated with ara-C, a chemotherapeutic agent. We undertook to use this reagent to reduce radioimmunotherapy(RAIT)-associated bone-marrow toxicity by suppressing hematopoiesis during the critical period when bone marrow is exposed to radiation. The reported studies optimize the use of HP5b to reduce the duration of neutropenia and thrombocytopenia. We found that 3.6 micrograms/day of HP5b administered through a continuous 7d mini-osmotic pump, together with a bolus dose of 3.6 micrograms 3 hours before the radioantibody dose, gave the best effect, as measured by neutrophil counts on day 28 post RAIT. With sub-lethal doses of RAIT, the period of neutropenia was reduced by 2 weeks, and there appeared to be more rapid recovery of morphologically mature myeloid cells. The peptide, however, does not appear to alleviate the lymphotoxicity associated with RAIT. No adverse effects have been noted from continuous infusions of the peptide. In the past, we reported that cytokines (IL-I/GM-CSF) are not marrow-restorative when given after RAIT. However, an additive effect is observed when HP5b infusions are combined with post-RAIT cytokine administration, suggesting that a significant pool of bone-marrow progenitor cells remains when HP5b is co-administered with RAIT. Thus, HP5b is an alternate approach to reducing myelotoxicity, and may be used in combination with cytokines to further reduce the duration of myelosuppression.
血液调节肽pGlu-Glu-Asp-Cys-Lys（pEEDCK或HP5b）已被证明可可逆地抑制骨髓祖细胞的增殖，并且据报道可保护小鼠免受与化疗药物阿糖胞苷相关的骨髓毒性。我们试图使用该试剂通过在骨髓暴露于辐射的关键时期抑制造血来降低放射免疫疗法（RAIT）相关的骨髓毒性。已报道的研究优化了HP5b的使用以缩短中性粒细胞减少和血小板减少的持续时间。我们发现，通过连续7天的微型渗透泵每天给予3.6微克HP5b，并在给予放射抗体剂量前3小时给予3.6微克的推注剂量，以RAIT后第28天的中性粒细胞计数衡量，效果最佳。对于亚致死剂量的RAIT，中性粒细胞减少期缩短了2周，并且形态学上成熟的髓样细胞似乎恢复得更快。然而，该肽似乎并未减轻与RAIT相关的淋巴细胞毒性。连续输注该肽未观察到不良反应。过去，我们报道过细胞因子（IL-1/GM-CSF）在RAIT后给予时对骨髓没有恢复作用。然而，当HP5b输注与RAIT后细胞因子给药联合使用时观察到相加效应，这表明当HP5b与RAIT联合给药时仍有大量骨髓祖细胞存在。因此，HP5b是降低骨髓毒性的一种替代方法，并且可与细胞因子联合使用以进一步缩短骨髓抑制的持续时间。
