Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Cancer. 2018 Oct 1;124(19):3890-3899. doi: 10.1002/cncr.31676. Epub 2018 Oct 9.
Calcitriol, the active analogue of vitamin D, is antiproliferative and enhances the cytotoxicity of several anticancer agents, including gemcitabine. The vitamin D receptor (VDR) is expressed in the tumor stroma and treatment with VDR ligands results in stromal remodeling and increased intratumoral gemcitabine delivery. Furthermore, calcitriol can decrease the activity of the gemcitabine deactivating enzyme cytidine deaminase (CDD). Because hypercalcemia has been the most worrisome calcitriol-related adverse event, the less hypercalcemic agent paricalcitol may be preferred for further investigation.
The authors undertook a phase 1 study of gemcitabine in combination with escalating doses of paricalcitol administered weekly intravenously in patients with advanced cancers. A standard 3+3 dose escalation schema was used. Pharmacokinetic assessment of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine (dFdU) was performed. Pharmacodynamic assessment of paricalcitol was performed by measurement of CDD activity in peripheral blood mononuclear cells.
A total of 44 patients were enrolled. Somnolence was the main dose-limiting toxicity. The highest dose of paricalcitol administered was 10.5 µg/kg. Hypercalcemia was infrequent and mild in severity. Paricalcitol did not appear to affect the pharmacokinetics of gemcitabine and dFdU. Evaluation of CDD activity was available for 9 patients; no clear trend for CDD activity after treatment with paricalcitol was established. The overall response rate was 4%; the rate of disease control was 67% in patients who were pretreated with gemcitabine. Progression-free and overall survival were 3.4 months and 6.5 months, respectively.
Paricalcitol can be administered safely in doses up to 7 µg/kg weekly with fixed dose rate gemcitabine without dose-limiting hypercalcemia. To the best of the authors' knowledge, the maximum tolerated dose has not been formally established to date. Preliminary clinical activity deserves further exploration.
活性维生素 D 类似物骨化三醇具有抗增殖作用，并可增强多种抗癌药物的细胞毒性，包括吉西他滨。维生素 D 受体（VDR）在肿瘤基质中表达，用 VDR 配体治疗可导致基质重塑和肿瘤内吉西他滨递呈增加。此外，骨化三醇可以降低吉西他滨失活酶胞苷脱氨酶（CDD）的活性。由于高钙血症一直是最令人担忧的骨化三醇相关不良事件，因此较少引起高钙血症的药物帕立骨化醇可能更适合进一步研究。
作者进行了一项吉西他滨联合帕立骨化醇递增剂量每周静脉给药治疗晚期癌症患者的 1 期研究。采用标准的 3+3 剂量递增方案。对吉西他滨及其代谢物 2',2'-二氟脱氧尿苷（dFdU）进行药代动力学评估。通过测量外周血单核细胞中 CDD 活性来评估帕立骨化醇的药效学。
共入组 44 例患者。嗜睡是主要的剂量限制毒性。给予的最高帕立骨化醇剂量为 10.5 µg/kg。高钙血症罕见且程度较轻。帕立骨化醇似乎不影响吉西他滨和 dFdU 的药代动力学。对 9 例患者的 CDD 活性进行了评估；但未能确立帕立骨化醇治疗后 CDD 活性的明确趋势。总缓解率为 4%；在预先使用吉西他滨的患者中，疾病控制率为 67%。无进展生存期和总生存期分别为 3.4 个月和 6.5 个月。
每周给予高达 7 µg/kg 的帕立骨化醇与固定剂量率吉西他滨联合使用是安全的，不会发生剂量限制的高钙血症。据作者所知，最大耐受剂量尚未正式确定。初步临床活性值得进一步探索。
