Kolber D L, Knisely T L, Maione T E
J Natl Cancer Inst. 1995 Feb 15;87(4):304-9. doi: 10.1093/jnci/87.4.304.
When administered locally, recombinant platelet factor 4 (rPF4), a known angiogenesis inhibitor, has been shown to effectively suppress murine melanoma and human colon carcinoma primary tumor growth in mice. It was tentatively concluded that this effect was due to the inhibition of tumor neovascularization.
This study has evaluated the effects of systemically administered rPF4 on the growth and establishment of experimental B16F10 melanoma lung metastases in syngeneic mice.
B16F10 cells (0.5-1.0 x 10(5) were administered intravenously to mice; 21 days later, the lungs were removed and the tumor foci were counted. Treatments with rPF4 were given to C57BL/6J mice immediately following tumor inoculation either (a) intravenously as a single dose (0.375, 0.75, 1.5, or 2.0 mg) or as multiple doses (6 mg total) over a 48-hour period, (b) subcutaneously or intramuscularly as multiple doses (6 mg total) over a 72-hour period, or (c) subcutaneously as multiple doses (6 mg total) over a 92- or 96-hour period following a delay of 4, 24, or 48 hours. (BALB/cByJ x C57BL/6)F1 (CByB6F1/J) athymic nude mice received rPF4 subcutaneously over a 72-hour period. The ability of rPF4 to block binding of 51Cr-labeled B16F10 tumor cells to matrix-coated microtiter plates was evaluated in vitro. The in vivo effect of intravenously injected rPF4 on the retention of 51Cr-labeled B16F10 cells was examined by determining the remaining lung-associated radioactivity after 30 minutes or 1, 2, or 4 hours.
Intravenous administration of rPF4 significantly inhibited the development of metastatic lung nodules in a dose-dependent fashion as assessed by both lesion number (P < .03) and lung weight (P < .05). When initiation of subcutaneous treatment with rPF4 was delayed 24-48 hours, the number of metastatic foci was significantly reduced (P < .05). The antitumor effect of rPF4 was not dependent on a T-lymphocyte-mediated process, since subcutaneous rPF4 treatment also suppressed the number of lung metastases in T-cell-deficient athymic CByB6F1/J nude mice. In vitro experiments demonstrated modest inhibitory effects (28%) of rPF4 on B16F10 tumor cell binding to purified murine vitronectin. However, lung clearance experiments at early time points (0.5 hour and 1 hour) showed that tumor lodging was not affected by rPF4 treatment.
The administration of rPF4 by systemic routes inhibited the development of experimental lung metastases. These findings are consistent with the known angiostatic properties of rPF4, and we conclude that inhibition of metastatic tumor formation may be due to inhibition of tumor-induced neovascularization.
These results support the testing of rPF4 as an angiostatic agent in the treatment of metastatic tumors.
已知重组血小板因子4（rPF4）是一种血管生成抑制剂，局部给药时，已证明其能有效抑制小鼠黑色素瘤和人结肠癌在小鼠体内的原发性肿瘤生长。初步得出结论，这种作用是由于抑制了肿瘤新生血管形成。
本研究评估了全身给药的rPF4对同基因小鼠实验性B16F10黑色素瘤肺转移生长和形成的影响。
将B16F10细胞（0.5 - 1.0×10⁵）静脉注射给小鼠；21天后，取出肺脏并计数肿瘤病灶。rPF4处理在肿瘤接种后立即给予C57BL/6J小鼠，给药方式如下：（a）静脉注射单剂量（0.375、0.75、1.5或2.0 mg）或在48小时内多次给药（总量6 mg）；（b）皮下或肌肉注射，在72小时内多次给药（总量6 mg）；或（c）在延迟4、24或48小时后，皮下多次给药（总量6 mg），给药时间为92或96小时。（BALB/cByJ×C57BL/6）F1（CByB6F1/J）无胸腺裸鼠在72小时内皮下注射rPF4。在体外评估rPF4阻断⁵¹Cr标记的B16F10肿瘤细胞与基质包被的微量滴定板结合的能力。通过测定30分钟或1、2或4小时后剩余的肺相关放射性，检查静脉注射rPF4对⁵¹Cr标记的B16F10细胞滞留的体内作用。
通过病灶数量（P <.03）和肺重量（P <.05）评估，静脉注射rPF4以剂量依赖方式显著抑制转移性肺结节的形成。当rPF4皮下治疗开始延迟24 - 48小时时，转移灶数量显著减少（P <.05）。rPF4的抗肿瘤作用不依赖于T淋巴细胞介导的过程，因为皮下注射rPF4也能抑制T细胞缺陷的无胸腺CByB6F1/J裸鼠的肺转移数量。体外实验表明，rPF4对B16F10肿瘤细胞与纯化的小鼠玻连蛋白结合有适度抑制作用（28%）。然而，早期时间点（0.5小时和1小时）的肺清除实验表明，rPF4处理不影响肿瘤着床。
全身途径给药rPF4可抑制实验性肺转移的发展。这些发现与rPF4已知的血管生成抑制特性一致，我们得出结论，转移性肿瘤形成的抑制可能是由于肿瘤诱导的新生血管形成受到抑制。
这些结果支持将rPF4作为血管生成抑制剂用于转移性肿瘤治疗的测试。
