DNA flow cytometric study of 5-fluorouracil used to treat end stage non-Hodgkin's lymphoma.
DNA flow cytometric study of 5-fluorouracil used to treat end stage non-Hodgkin's lymphoma.
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用于治疗终末期非霍奇金淋巴瘤的 5-氟尿嘧啶的 DNA 流式细胞术研究。
作者：
D. Hedley
无论组织学亚型如何，非霍奇金淋巴瘤（NHL）化疗的进一步改进需要开发新的有效药物或更好地使用现有药物，这是不言自明的。按照惯例，如果在一定比例的患者中观察到可测量疾病大小的客观减少，则认为细胞毒性药物对特定肿瘤类型具有活性。然而，在某些情况下，明显无活性的药物可能与其适当的细胞内靶点相互作用，但不能产生任何临床可检测的作用。“亚临床反应”可能是潜在的好处，如果药物与第二种药物，它与协同作用，特别是如果这种增效作用是肿瘤特异性的。最近，对5-氟尿嘧啶（5-FU）的兴趣重新抬头，有证据表明其作用可以通过例如与甲氨蝶呤组合而显著增强（Bertino等人，1977）或顺铂（Kish等，1984年）。尽管5-FU被认为是治疗NHL的非活性药物（Heidelberger，1982），但治疗和随后报告的患者总数很少，并且早期文献实际上显示了一些反应（Ansfield等人，1962; Krivit & Bentley，1960）。因此，重新评估其治疗NHL的单药活性似乎是及时的。5-FU处理可抑制DNA和RNA的合成，前者是由于阻断胸苷酸合成酶所致。除了常规的临床反应标准，5-FU干扰DNA合成的能力，因此，通过使用流式细胞术来测量细胞DNA含量的顺序细针从肿瘤吸出物进行评估。4例终末期耐药NHL患者接受5-FU治疗，其临床详情总结见表I。弥漫性大细胞淋巴瘤2例，弥漫性高分化淋巴细胞淋巴瘤2例。所有患者均患有可测量的症状性疾病，尽管之前接受过多次细胞毒性药物治疗，但患者仍表示希望尝试进一步化疗，并口头同意从肿瘤沉积物中进行多次细针抽吸。治疗包括5-FU，1，000 mg m2，第1天，连续静脉输注4天，但1例患者（Al）除外，该患者因既存血小板减少症仅接受了3天输注。除了肿瘤沉积物的大小之外，还使用流式细胞术测量细胞DNA含量。在治疗前从可触及部位采集细针（23号）抽吸物。在三种情况下，获得了足够量的DNA流式细胞术材料（即105-106个有核细胞）。第4例患者（Al）有多个淋巴结，这些淋巴结太小，无法进行令人满意的细针穿刺，但也有外周血淋巴细胞增多症（淋巴细胞绝对计数6 x 1001-1）和淋巴结组织学检查，显示分化良好的弥漫性淋巴细胞淋巴瘤。因此，使用外周血代替流式细胞术。在所有情况下，
Irrespective of histological sub-type, it is axiomatic that further improvements in the chemotherapy of non-Hodgkin's lymphomas (NHL) require either the development of new effective drugs or the better use of existing agents. By convention, a cytotoxic drug is considered to have activity against a particular tumour type if objective decreases in the size of measurable disease are observed in a proportion of patients. In some instances however an apparently inactive drug may interact with its appropriate intracellular target but fail to produce any clinically detectable effect. 'Subclinical responses' might be of potential benefit if the drug were to be combined with a second agent with which it acted synergistically, especially if this potentiation were tumour-specific. Recently there has been a resurgence of interest in 5fluorouracil (5-FU), with evidence that its action may be markedly potentiated by combination for example with methotrexate (Bertino et al., 1977) or cis-platin (Kish et al., 1984). Although 5-FU is considered an inactive drug in the treatment of NHL (Heidelberger, 1982), the total number of patients treated and subsequently reported is small, and the earlier literature does in fact show some responses (Ansfield et al., 1962; Krivit & Bentley, 1960). It therefore seemed timely to re-assess its single agent activity in the treatment of NHL. Both DNA and RNA synthesis can be inhibited by 5-FU treatment, the former resulting from blockade of thymidylate synthetase. In addition to conventional clinical criteria for response, the ability of 5-FU to perturb DNA synthesis was therefore assessed by using flow cytometry to measure the cellular DNA content of sequential fine needle aspirates from the tumour. Four patients with end stage, drug resistant NHL were treated with 5-FU, and their clinical details are summarised in Table I. Two had diffuse large cell lymphoma, and two well differentiated diffuse lymphocytic lymphoma. All had measurable symptomatic disease, and despite numerous previous courses of cytotoxic drugs expressed a desire to try further chemotherapy and gave verbal informed consent for multiple fine needle aspirates from tumour desposits. Treatment comprised 5-FU, 1,000 mg m2 day1 given as a continuous i.v. infusion for 4 days except in one patient (Al), who received only a 3-day infusion because of pre-existing thrombocytopaenia. In addition to the size of tumour deposits, measurements were made of cellular DNA content using flow cytometry. Fine needle (23 gauge) aspirates were taken from accessible sites pre-treatment. In three cases an adequate amount of material for DNA flow cytometry (i.e. 105-106 nucleated cells) was obtained. The fourth patient (Al) had multiple lymph nodes which were too small for satisfactory fine needle aspiration, but also had a peripheral blood lymphocytosis (absolute lymphocyte count 6 x 1001-1) and lymph node histology which showed well differentiated diffuse lymphocytic lymphoma. Peripheral blood was therefore used instead for flow cytometry. In all cases material was