Blumenthal R D, Sharkey R M, Haywood L, Behr T, Goldenberg D M
Garden State Cancer Center at the Center for Molecular Medicine and Immunology, Belleville, NJ 07109, USA.
Int J Cancer. 1997 Jul 3;72(1):166-73. doi: 10.1002/(sici)1097-0215(19970703)72:1<166::aid-ijc24>3.0.co;2-g.
The goal of our studies was to determine whether administration of IL-1/GM-CSF to mice could reduce radio-antibody-induced myelosuppression and allow either dose escalation of radio-antibody using 131I, 90Y or 188Re conjugated to either intact antibody or bivalent fragments or more frequent dosing with 131I-IgG. Survival, peripheral blood counts, hematopoietic tissue weight and number of marrow CFCs were used to determine the ability to dose-intensify with a single dose or to reduce the spacing between doses. In this report, we show that in the absence of cytokines, 2 cycles of 131I-IgG spaced at 28, 35, 42 and 49 days resulted in 100%, 100%, 40% and 0% lethality, respectively. In contrast, cytokine intervention reduced lethality to 45%, 20%, 0% and 0% at the same time intervals between doses. Thus, the use of cytokines permits at least a 1 week earlier redosing of 131I-IgG. Cytokine intervention also has reduced the magnitude of myelosuppression, as measured by neutropenia and thrombocytopenia, thus permitting intensification of single doses of radio-iodinated intact antibodies, bivalent fragments and 90Y-IgG by at least 30%, 50% and 25%, respectively. However, cytokines were not effective at permitting dose escalation of either 90Y-F(ab')2 or 188Re-IgG. Further optimization of the dose schedule of cytokine administration needs to be explored for these 2 nuclide-antibody forms.
我们研究的目标是确定给小鼠注射白细胞介素-1/粒细胞巨噬细胞集落刺激因子（IL-1/GM-CSF）是否能减轻放射性抗体诱导的骨髓抑制，并允许使用与完整抗体或二价片段偶联的131I、90Y或188Re进行放射性抗体剂量递增，或更频繁地注射131I-IgG。通过生存情况、外周血细胞计数、造血组织重量和骨髓集落形成细胞（CFC）数量来确定单剂量增加剂量或减少给药间隔的能力。在本报告中，我们表明，在没有细胞因子的情况下，间隔28、35、42和49天进行2个周期的131I-IgG注射，致死率分别为100%、100%、40%和0%。相比之下，在相同的给药间隔时间，细胞因子干预使致死率降至45%、20%、0%和0%。因此，使用细胞因子可使131I-IgG至少提前1周重新给药。细胞因子干预还降低了以中性粒细胞减少和血小板减少衡量的骨髓抑制程度，从而允许分别将单剂量的放射性碘化完整抗体、二价片段和90Y-IgG的剂量增加至少30%、50%和25%。然而，细胞因子在允许90Y-F(ab')2或188Re-IgG剂量递增方面无效。对于这两种核素-抗体形式，需要进一步探索细胞因子给药剂量方案的优化。
