Kohn E C, Liotta L A
Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland 28092, USA.
Cancer Res. 1995 May 1;55(9):1856-62.
The diagnosis and treatment of solid tumors usually begins at a late stage when most patients already have occult or overt metastasis. Many years of cancer progression precede diagnosis of most solid tumors. Novel noncytotoxic therapeutics may be specially suited for administration during this interval. An important window of intervention can be defined as the period during which transition from a hyperproliferative state to acquisition of the capacity for invasion and metastasis occurs. Investigation of the molecular basis of invasion is uncovering strategies for delaying progression of preinvasive carcinoma and treatment of primary tumors and established metastasis. Although tumor cell invasion might not be rate limiting for the growth of metastasis, anti-invasive agents can block tumor angiogenesis and thereby indirectly block metastasis growth. Two classes of molecular anti-invasion targets exist: (a) cell surface and extracellular proteins, which mediate sensing, adhesion, and proteolysis; and (b) signal transduction pathways, which regulate invasion, angiogenesis, and proliferation. Both categories of targets yield treatment approaches that are now being tested in the clinic. Metalloproteinase inhibitors, such as BB94, are based on the recognition that metalloproteinases play a necessary role in invasion and angiogenesis. The orally active signal transduction inhibitor carboxyamidotriazole modulates non-voltage-gated calcium influx-regulated signal pathways and reversibly inhibits tumor invasion, growth, and angiogenesis. Blockade of invasion, angiogenesis, or cellular signal pathways is likely to generate a cytostatic, rather than a cytotoxic effect. Cytostatic therapy constitutes an alternative paradigm for clinical translation that may complement conventional cytotoxic therapy. For patients with newly diagnosed solid tumors, long-term cytostatic therapy could potentially create a state of metastasis dormancy or delay the time to overt relapse following cytotoxic agent-induced remission. Clinical toxicity and pharmacology using oral cytostatic agents in phase I trials and in adjuvant settings will provide an important foundation for the translation of this approach to the preinvasive carcinoma period.
实体瘤的诊断和治疗通常始于晚期，此时大多数患者已经发生隐匿性或显性转移。多数实体瘤在诊断前已有多年的癌症进展过程。新型非细胞毒性疗法可能特别适合在这一期间使用。一个重要的干预窗口期可定义为从增殖活跃状态转变为获得侵袭和转移能力的时期。对侵袭分子基础的研究正在揭示延缓癌前病变进展以及治疗原发性肿瘤和已发生转移的策略。尽管肿瘤细胞侵袭可能不是转移灶生长的限速因素，但抗侵袭药物可阻断肿瘤血管生成，从而间接阻断转移灶的生长。存在两类分子抗侵袭靶点：（a）细胞表面和细胞外蛋白，它们介导感知、黏附及蛋白水解；（b）信号转导通路，其调节侵袭、血管生成和增殖。这两类靶点均产生了目前正在临床中进行试验的治疗方法。金属蛋白酶抑制剂，如BB94，是基于金属蛋白酶在侵袭和血管生成中起必要作用这一认识研发的。口服活性信号转导抑制剂羧甲氨基三唑可调节非电压门控钙内流调节的信号通路，并可逆性抑制肿瘤侵袭、生长和血管生成。阻断侵袭、血管生成或细胞信号通路可能产生细胞生长抑制作用，而非细胞毒性作用。细胞生长抑制疗法构成了一种可供临床转化的替代模式，可能补充传统的细胞毒性疗法。对于新诊断的实体瘤患者，长期细胞生长抑制疗法有可能产生转移灶休眠状态，或延迟细胞毒性药物诱导缓解后明显复发的时间。在I期试验及辅助治疗中使用口服细胞生长抑制药物的临床毒性和药理学研究将为将该方法应用于癌前病变期提供重要基础。
