Ray M S, Muggia F M, Leichman C G, Grunberg S M, Nelson R L, Dyke R W, Moran R G
Department of Medicine, University of Southern California, Los Angeles.
J Natl Cancer Inst. 1993 Jul 21;85(14):1154-9. doi: 10.1093/jnci/85.14.1154.
Cancer chemotherapy with folate antimetabolites has been traditionally targeted at the enzyme dihydrofolate reductase and is based on the requirement of dividing tumor cells for a supply of thymidylate and purines. However, a new compound, 5,10-dideazatetrahydrofolate (DDATHF, whose 6R diastereomer is also known as Lometrexol), has become available that prevents tumor cell growth by inhibiting the first of the folate-dependent enzymes involved in de novo purine synthesis, glycinamide ribonucleotide formyltransferase.
We investigated the toxicity and therapeutic activity of DDATHF in a phase I clinical trial.
DDATHF was given at one of the following dose levels to 33 patients (16 females and 17 males) with malignant solid tumors: 3.0 mg/m2 per week (level A) to 10 patients, 4.5 mg/m2 per week (level B) to 13 patients, or 6.0 mg/m2 per week (level C) to 10 patients. Each drug cycle consisted of three weekly injections of DDATHF followed by a 2-week rest prior to redosing in the next cycle.
Of 33 patients, 27 received at least one full cycle of DDATHF. Thrombocytopenia was the major dose-limiting toxicity, and it was severe in one of 10 patients during the first cycle and in two of four patients during the second cycle. Because of cumulative toxicity at 6.0 mg/m2, second or later cycles were abbreviated to two weekly doses. Stomatitis was generally mild, but it was dose-limiting in one patient. Neutropenia was infrequent and mild, and normocytic anemia requiring blood transfusion was common with repeat dosing. Leucovorin was given for grade 2 or greater thrombocytopenia and resulted in hematologic recovery within 1 week in all eight patients so treated. Without leucovorin, the thrombocytopenia lasted from 7 to 49 days in three patients. A partial response was noted in one patient with non-small-cell lung cancer and a minor response in one patient with breast cancer. Three patients with colorectal cancer achieved stable disease for greater than 3 months with improvement in carcinoembryonic antigen levels in one patient.
DDATHF has an unusual pattern of toxicity with repetitive dosing, and humans with advanced cancer are considerably more sensitive than would be predicted from previous animal studies. Although doses of 6.0 mg/m2 per week on our schedule have been determined to be safe, repeated cycles require careful monitoring because of cumulative toxic effects.
Additional phase I studies of DDATHF that relate toxicity to folate intake and tissue folate pools appear warranted.
传统上，使用叶酸抗代谢物进行癌症化疗的靶点是二氢叶酸还原酶，其依据是分裂的肿瘤细胞需要供应胸苷酸和嘌呤。然而，一种新化合物5,10 - 二去氮四氢叶酸（DDATHF，其6R非对映异构体也被称为洛美曲索）已可获得，它通过抑制从头合成嘌呤过程中涉及的首个叶酸依赖性酶——甘氨酰胺核糖核苷酸甲酰基转移酶，来阻止肿瘤细胞生长。
我们在一项I期临床试验中研究了DDATHF的毒性和治疗活性。
将DDATHF以以下剂量水平之一给予33例（16例女性和17例男性）恶性实体瘤患者：每周3.0 mg/m²（A组），共10例患者；每周4.5 mg/m²（B组），共13例患者；或每周6.0 mg/m²（C组），共10例患者。每个药物周期包括每周注射三次DDATHF，然后休息2周，之后进入下一个周期重新给药。
33例患者中，27例接受了至少一个完整周期的DDATHF治疗。血小板减少是主要的剂量限制性毒性，在第一个周期中，10例患者中有1例严重，在第二个周期中，4例患者中有2例严重。由于6.0 mg/m²时的累积毒性，第二个周期及之后的周期缩短为每周两次给药。口腔炎一般较轻，但有1例患者出现剂量限制性毒性。中性粒细胞减少不常见且较轻，重复给药时常见需要输血的正细胞性贫血。对于2级或更高级别的血小板减少给予亚叶酸钙，所有8例接受治疗的患者在1周内血液学恢复。未使用亚叶酸钙时，3例患者的血小板减少持续7至49天。1例非小细胞肺癌患者出现部分缓解，1例乳腺癌患者出现轻微缓解。3例结直肠癌患者疾病稳定超过3个月，其中1例患者癌胚抗原水平有所改善。
DDATHF重复给药时具有不寻常的毒性模式，晚期癌症患者比先前动物研究预测的更为敏感。尽管按照我们的给药方案每周6.0 mg/m²的剂量已被确定为安全，但由于累积毒性作用，重复周期需要仔细监测。
似乎有必要对DDATHF进行更多将毒性与叶酸摄入和组织叶酸池相关联的I期研究。
