Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia.
Optimizing the use of combined radioimmunotherapy and hypoxic cytotoxin therapy as a function of tumor hypoxia.
复制标题
根据肿瘤缺氧情况优化放射免疫疗法和缺氧细胞毒素疗法的联合使用。
DOI：
10.1002/ijc.1500
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发表时间：
2001
影响因子：
6.4
通讯作者：
Goldenberg,DM
中科院分区：
文献类型：
--
作者：
Blumenthal,RD;Taylor,A;Osorio,L;Ochakovskaya,R;Raleigh,JA;Papadopoulou,M;Bloomer,WD;Goldenberg,DM
Combined radioimmunotherapy (RAIT) and hypoxic cytotoxin therapy (SR4233 or NLCQ‐1) have been evaluated with both modalities administered on the same day with only moderate improvement compared with the effects of RAIT alone. In a series of studies using oxygen electrodes, immunohistochemistry and radiotracers, we have demonstrated that RAIT induces a prolonged state of hypoxia in most tumors, without affecting the pO2levels in normal tissues. Using serial microelectrode measurements through subcutaneous (s.c.) GW‐39 human colonic xenografts, we established that the median pO2was unrelated to the initial size of the tumor, over a range of sizes from 1.0 to 4.0 cm. Fourteen days after mice were given a 240‐μCi dose of131I‐MN‐14 anti‐carcinoembryonic antigen immunoglobulin G, their median pO2declined from 26.1 ± 9.6 mmHg to 9.8 ± 3.9 mmHg (p< 0.001). Using the radiotracer3H‐MISO that accumulates in hypoxic regions, uptake in GW‐39, LoVo and LS174T s.c. human colonic tumors increased 3.0‐ to 4.2‐fold from day 14 through day 28 post‐RAIT, but uptake of3H‐MISO in CALU‐3 tumors remained unchanged after RAIT. Normal tissue (liver, kidney, lung) uptake of3H‐MISO did not exhibit significant changes. The increase in tumor hypoxia was also demonstrated visually using anti‐PIMO staining of tumor sections. We postulated that sequential delivery of the 2 therapeutic agents, with the hypoxic cytotoxin given 2 weeks after RAIT when tumor pO2levels were at their nadir, would improve the therapeutic response above either modality alone or above the 2 agents delivered on the same day. Tumor growth was compared in mice given either RAIT or cytotoxin alone, the combined treatment on the same day or with the cytotoxin delivered 14 days after RAIT. Tumor size on day 35 for RAIT‐treated and SR4233‐treated GW‐39 were 3.56 ± 0.40 and 7.98 ± 2.50 cm3. When RAIT + SR4233 were delivered on the same day, tumor size dropped to 2.78 ± 0.80 cm3. If RAIT was given on day 0 and SR4233 on day 14, size further declined further to 1.74 ± 0.32 cm3(p< 0.05 compared with same day delivery). For LS174T, tumor size on day 28 for RAIT‐treated and SR4233‐treated tumors were 1.14 ± 0.36 cm3and 3.65 ± 0.78 cm3, respectively. When RAIT + SR4233 were delivered on the same day, size was 0.51 ± 0.174 cm3. If RAIT was dosed on day 0 and SR4233 was given on day 14, tumor size was 0.13 ± 0.07 cm3(p< 0.05). Similar results were obtained for LoVo, but not for CALU‐3 tumors. Another hypoxic cytotoxin, NLCQ‐1, was also more efficacious 2 weeks after RAIT, compared with same‐day dosing. Thus, information on tumor hypoxia after radioantibody therapy could be important for ascertaining a window of opportunity when the surviving tumor regions are most responsive to hypoxic cytotoxins. © 2001 Wiley‐Liss, Inc.
