Vukanovic J, Isaacs J T
Johns Hopkins Oncology Center, Baltimore, Maryland 21231-1001, USA.
Cancer Res. 1995 Aug 15;55(16):3517-20.
Human prostatic cancer cells have a remarkably low rate of proliferation even when they have metastasized to the bone and have become androgen independent (Berges et al., Clin. Cancer Res., 1:473-480, 1995). Due to this low proliferation, patients with such androgen-independent metastatic prostatic cancer cells are rarely treated successfully with the presently available chemotherapeutic agents. Therefore, new approaches are urgently needed which are not dependent on the rate of cancer cell proliferation for their effectiveness. One such approach is to inhibit the angiogenic response within localized and metastatic cancer deposits, since the resultant hypoxia-induced tumor cell death does not require cell proliferation. We have previously demonstrated that the quinoline-3-carboxamide, linomide, is an p.o. active agent which inhibits tumor angiogenesis and thus blood flow in a variety of rat prostatic cancers independent of their growth rate, androgen sensitivity, or metastatic ability. Because of its antiangiogenic effects, linomide treatment induces the hypoxic death of rat prostatic cancer cells, thus inhibiting their net growth and metastases. To determine whether human prostatic cancer cells are similarly sensitive to hypoxia-induced death caused by linomide inhibition of tumor angiogenesis, androgen-independent TSU and PC-3 human prostatic cancer cells were xenotransplanted into SCID mice that were either untreated or treated p.o. with linomide. These studies demonstrated that linomide treatment decreases microvessel density in both androgen-independent human prostatic cancers. Microvessel density was decreased from 1.8 +/- 0.4% of the total area in control tumors to 1.0 +/- 0.2% in linomide-treated TSU tumors [i.e., a 44% decrease in microvessel density (P < 0.05)]. Similarly, a 56% decrease (P < 0.05) was observed in the microvessel density of PC-3 tumors (i.e., 2.7 +/- 0.8% of the area in control tumor versus 1.2 +/- 0.2% in the linomide-treated tumors). This inhibition of angiogenesis increased cell death in both TSU and PC-3 cancer cells. This is reflected in both an increase in the area of necrosis and an increase in the apoptotic index in non-necrotic areas. In untreated TSU tumors, 40 +/- 2% of tumor volume was necrotic. Linomide treatment increased this necrotic percentage to 59 +/- 2% [i.e., 48% increase (P < 0.05)]. Linomide therapy also increased apoptotic cell death in non-necrotic tumor areas. In the untreated TSU tumors, 2.9 +/- 0.6% of tumor cells were apoptotic in the non-necrotic areas, and in the linomide-treated TSU tumors this percentage increased to 3.6 +/- 0.4% [i.e., 24% increase (P < 0.05)].(ABSTRACT TRUNCATED AT 400 WORDS)
人类前列腺癌细胞即使已经转移到骨骼且变为雄激素非依赖性，其增殖速率也非常低（Berges等人，《临床癌症研究》，1:473 - 480，1995）。由于这种低增殖率，患有此类雄激素非依赖性转移性前列腺癌细胞的患者很少能用目前可用的化疗药物成功治疗。因此，迫切需要新的方法，其有效性不依赖于癌细胞的增殖速率。一种这样的方法是抑制局部和转移性癌灶内的血管生成反应，因为由此产生的缺氧诱导的肿瘤细胞死亡不需要细胞增殖。我们之前已经证明，喹啉 - 3 - 甲酰胺类药物利诺胺是一种口服活性药物，它能抑制多种大鼠前列腺癌的肿瘤血管生成，从而抑制血流，而与它们的生长速率、雄激素敏感性或转移能力无关。由于其抗血管生成作用，利诺胺治疗可诱导大鼠前列腺癌细胞的缺氧死亡，从而抑制其净生长和转移。为了确定人类前列腺癌细胞是否对利诺胺抑制肿瘤血管生成所导致的缺氧诱导死亡同样敏感，将雄激素非依赖性的TSU和PC - 3人类前列腺癌细胞异种移植到未治疗或口服利诺胺治疗的SCID小鼠体内。这些研究表明，利诺胺治疗可降低两种雄激素非依赖性人类前列腺癌中的微血管密度。在对照肿瘤中微血管密度占总面积的1.8±0.4%，在利诺胺治疗的TSU肿瘤中降至1.0±0.2%[即微血管密度降低了44%（P < 0.05）]。同样，在PC - 3肿瘤的微血管密度中观察到降低了56%（P < 0.05）（即对照肿瘤中占面积的2.7±0.8%，而在利诺胺治疗的肿瘤中为1.2±0.2%）。这种血管生成的抑制增加了TSU和PC - 3癌细胞的死亡。这体现在坏死面积的增加和非坏死区域凋亡指数的增加上。在未治疗的TSU肿瘤中，40±2%的肿瘤体积是坏死的。利诺胺治疗使这个坏死百分比增加到59±2%[即增加了48%（P < 0.05）]。利诺胺治疗还增加了非坏死肿瘤区域的凋亡细胞死亡。在未治疗的TSU肿瘤中，非坏死区域2.9±0.6%的肿瘤细胞是凋亡的，而在利诺胺治疗的TSU肿瘤中这个百分比增加到3.6±0.4%[即增加了24%（P < 0.05）]。（摘要截断于400字）
