Talpaz M, Plager C, Quesada J, Benjamin R, Kantarjian H, Gutterman J
Eur J Cancer Clin Oncol. 1986 Jun;22(6):685-9. doi: 10.1016/0277-5379(86)90166-5.
Difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and human leukocyte interferon (IFN-alpha) have synergistic anti-tumor activities in vivo in B 16 melanoma and in vitro against several human cancer cell lines. We have, therefore, carried out a phase I combination study with DFMO plus alpha interferon in the following manner: DFMO was maintained at a steady dose for the first four levels, 1.5 g/m2 every 6 hr. IFN-alpha was given in 100% increments ranging from 0.4 X 10(6)U/m2 to 3.2 X 10(6)U/m2 i.m. daily. At the fifth dose level both IFN-alpha and DFMO were raised by 100 and 50% respectively. From levels one through four the combination was well tolerated with no dose interruptions required because of G.I. toxicity or myelosuppression. However, at dose level 5, one-third of the patients required dose cessation and decrease due to nausea, vomiting and diarrhea. We conclude that for phase II studies the maximal tolerated dose is 3.2 million units of IFN-alpha/m2 and 1.5 g/m2 of DFMO every 6 hr. Of 12 patients with metastatic melanoma, 2 had partial remissions lasting 58+ and 36+ weeks. Two additional patients had minor responses lasting 29 and 32+ weeks. Minor responses were observed in a patient with colon carcinoma and a patient with renal carcinoma. The clinical activity of the combination is currently being pursued in a phase II study among patients with metastatic malignant melanoma.
二氟甲基鸟氨酸（DFMO）是鸟氨酸脱羧酶的不可逆抑制剂，与人类白细胞干扰素（IFN-α）在体内对B16黑色素瘤以及在体外对多种人类癌细胞系具有协同抗肿瘤活性。因此，我们以如下方式开展了DFMO加α干扰素的I期联合研究：在前四个剂量水平，DFMO维持稳定剂量，每6小时1.5g/m²。IFN-α每日肌肉注射，剂量以100%递增，范围从0.4×10⁶U/m²至3.2×10⁶U/m²。在第五个剂量水平，IFN-α和DFMO分别提高100%和50%。从第一至第四剂量水平，联合用药耐受性良好，无需因胃肠道毒性或骨髓抑制而中断剂量。然而，在剂量水平5时，三分之一的患者因恶心、呕吐和腹泻需要停药和减量。我们得出结论，对于II期研究，最大耐受剂量是IFN-α 320万单位/m²以及每6小时DFMO 1.5g/m²。12例转移性黑色素瘤患者中，2例出现部分缓解，持续时间分别为58 +周和36 +周。另外2例患者有微小反应，持续时间分别为29周和32 +周。在1例结肠癌患者和1例肾癌患者中观察到微小反应。目前正在对转移性恶性黑色素瘤患者开展II期研究，以探索该联合用药的临床活性。
