Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
Clin Cancer Res. 2015 May 1;21(9):2107-14. doi: 10.1158/1078-0432.CCR-14-2298. Epub 2015 Feb 12.
Chemotherapy targets rapidly proliferating tumor cells, but spares slowly proliferating hypoxic cells. We hypothesized that nutrition of hypoxic cells would improve in intervals between chemotherapy, and that hypoxic cells destined to die without treatment would survive and proliferate.
We therefore evaluated repopulation and reoxygenation following chemotherapy, and the effects of the hypoxia-activated prodrug TH-302 on these processes. Tumor-bearing mice were treated with doxorubicin or docetaxel ± TH-302. Pimonidazole (given concurrent with chemotherapy) and EF5 (given 24 to 120 hours later) identified hypoxic cells. Proliferation (Ki67) and oxygen status (EF5 uptake) of formerly hypoxic (pimo positive) cells were quantified by immunohistochemistry.
Chronically hypoxic cells had limited proliferation in control tumors. After chemotherapy, we observed reoxygenation and increased proliferation of previously hypoxic cells; these processes were inhibited by TH-302.
Chemotherapy leads to paradoxical sparing of hypoxic cells destined to die in solid tumors in absence of treatment, and their reoxygenation and proliferation: TH-302 inhibits these processes.
化疗针对快速增殖的肿瘤细胞，但不会影响缓慢增殖的缺氧细胞。我们假设，在化疗间隔期间，缺氧细胞的营养供应会得到改善，而且没有接受治疗注定会死亡的缺氧细胞将会存活并增殖。
因此，我们评估了化疗后肿瘤细胞的再增殖和再氧合作用，以及缺氧激活前药 TH-302 对这些过程的影响。荷瘤小鼠接受多柔比星或多西他赛治疗，加或不加 TH-302。在化疗同时给予 pimonidazole（用于鉴定缺氧细胞）和 EF5（在化疗后 24 至 120 小时给予）。通过免疫组织化学定量分析先前缺氧（pimo 阳性）细胞的增殖（Ki67）和氧状态（EF5 摄取）。
在对照肿瘤中，慢性缺氧细胞的增殖能力有限。化疗后，我们观察到先前缺氧细胞的再氧合和增殖增加；这些过程被 TH-302 抑制。
化疗导致在没有治疗的情况下，实体瘤中注定死亡的缺氧细胞出现矛盾性的保护，并且它们的再氧合和增殖：TH-302 抑制这些过程。
