Saven A, Kawasaki H, Carrera C J, Waltz T, Copeland B, Zyroff J, Kosty M, Carson D A, Beutler E, Piro L D
Department of Radiology, Ida M. and Cecil H. Green Cancer Center, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
J Clin Oncol. 1993 Apr;11(4):671-8. doi: 10.1200/JCO.1993.11.4.671.
We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses.
Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis.
Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness.
The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.
我们对实体瘤患者进行了2-氯脱氧腺苷（2-CdA）的剂量递增研究，以确定最大耐受剂量（MTD），并明确其在更高剂量下的毒性特征。
21例患者入组本研究，其中7例为恶性星形细胞瘤，12例为转移性黑色素瘤，2例为转移性肾细胞癌。患者按队列接受治疗，每28天连续静脉输注2-CdA，剂量分别为0.10、0.15或0.20mg/kg/d，共7天。通过放射免疫分析法测定2-CdA水平。在肿瘤组织样本中，通过酶活性和免疫反应性蛋白分析测定脱氧胞苷激酶（dCK）水平。
7例接受0.1mg/kg/d 2-CdA治疗的患者中，1例出现3级或4级骨髓毒性。11例接受0.15mg/kg/d治疗的患者中，4例出现骨髓毒性，2例在接受单疗程2-CdA治疗后出现。所有3例接受0.2mg/kg/d 2-CdA治疗的患者均出现骨髓抑制。2例患者出现神经系统事件，均为恶性黑色素瘤患者。7例星形细胞瘤患者中有2例（28.6%）获得部分缓解，中位缓解持续时间为8个月。2-CdA可穿透血脑屏障。通过酶活性和免疫反应性蛋白测定的dCK水平之间存在关联，但这与2-CdA的肿瘤反应性无关。
对于非血液系统恶性肿瘤患者，2-CdA连续静脉输注7天的MTD确定为0.1mg/kg/d，与血液系统恶性肿瘤患者的MTD相同。dCK表达与对2-CdA的反应之间无临床相关性。恶性星形细胞瘤患者中观察到的反应值得进一步开展II期研究。
