Blumenthal R D, Reising A, Lew W, Dunn R, Ying Z, Goldenberg D M
Garden State Cancer Center, Belleville, New Jersey, USA.
Eur J Cancer. 1999 May;35(5):815-24. doi: 10.1016/s0959-8049(98)00432-8.
The temporal variation in bone marrow proliferation has been used to help define the optimal time of day to dose with approximately 30 chemotherapeutic agents, so that treatment efficacy is maximised and toxicity is minimised. Since myelosuppression is also the dose-limiting toxicity for most forms of radioimmunotherapy, we hypothesised that time of day of administration might also influence tolerance for radioantibody therapy. Bone marrow proliferative activity in BALB/c mice was determined using cell cycle analysis of propidium iodide-stained bone marrow samples collected at 3 h intervals. Myelosuppression was determined at weekly intervals after a therapeutic dose of 131I-NP-4 anti-CEA (carcinoembryonic antigen) intact IgG at either 0900 h (2 h after light onset [HALO]), 1300 h (6 HALO) or 1600 h (9 HALO). The highest bone marrow proliferative activity was noted between 20 HALO (0300 h) and 4 HALO (1100 h), and the lowest activity could be measured at 10-13 HALO (1700-2000 h). Seven days after a maximal tolerated dose (MTD) of radioantibody, granulocyte reduction was 50% at both 2 and 6 HALO and only 32% at 9 HALO (P < 0.003). Fourteen days after radioantibody therapy, an 87% granulocyte suppression was observed in mice treated at 2 HALO and only a 64% granulocyte loss was noted in the 9 HALO treated group (P < 0.001). The 2 HALO group recovered earlier than the 9 HALO group (P < 0.013; 22% loss from the 2 HALO dose and 40% loss from the 9 HALO dose) on day 28 post-radioimmunotherapy. The difference in magnitude of neutropenia, rather than duration, was critical for establishing the MTD. A 30% increase in the MTD was possible if mice were dosed at 9 HALO (320 microCi) versus 2 HALO (240 microCi). These studies suggest that principles of chronobiology may govern the magnitude of toxicity and the highest dose tolerated in radioantibody therapy in the same way that it does for cytotoxic drug therapy.
骨髓增殖的时间变化已被用于确定约30种化疗药物给药的最佳时间，以便使治疗效果最大化，毒性最小化。由于骨髓抑制也是大多数形式的放射免疫疗法的剂量限制性毒性，我们推测给药时间也可能影响放射抗体治疗的耐受性。使用对每隔3小时采集的碘化丙啶染色骨髓样本进行细胞周期分析，来确定BALB/c小鼠的骨髓增殖活性。在0900时（光照开始后2小时[HALO]）、1300时（6 HALO）或1600时（9 HALO）给予治疗剂量的131I-NP-4抗癌胚抗原（CEA）完整IgG后，每周间隔测定骨髓抑制情况。在光照后20小时（0300时）至4小时（1100时）之间观察到最高的骨髓增殖活性，而在光照后10 - 13小时（1700 - 2000时）可测得最低活性。给予放射抗体最大耐受剂量（MTD）7天后，在2 HALO和6 HALO时粒细胞减少均为50%，而在9 HALO时仅为32%（P < 0.003）。放射抗体治疗14天后，在2 HALO治疗的小鼠中观察到87%的粒细胞抑制，而在9 HALO治疗组中仅观察到64%的粒细胞损失（P < 0.001）。在放射免疫治疗后第28天，2 HALO组比9 HALO组恢复得更早（P < 0.013；2 HALO剂量组损失22%，9 HALO剂量组损失40%）。中性粒细胞减少的程度差异而非持续时间，对于确定MTD至关重要。如果小鼠在9 HALO（320微居里）给药而非2 HALO（240微居里）给药，MTD可能增加30%。这些研究表明，时间生物学原理可能像对细胞毒性药物治疗一样，控制放射抗体治疗中的毒性程度和最高耐受剂量。
