Veenhuizen R, Oppelaar H, Ruevekamp M, Schellens J, Dalesio O, Stewart F
Experimental Therapy Division, Netherlands Cancer Institute/Antoni van Leeuwenhoek Huis, Amsterdam, The Netherlands.
Int J Cancer. 1997 Oct 9;73(2):236-9. doi: 10.1002/(sici)1097-0215(19971009)73:2<236::aid-ijc13>3.0.co;2-d.
Preferential retention of photosensitizers in tumours has always been one of the major goals in the search for new photosensitizers and has determined the design of clinical trials with respect to the interval between drug administration and illumination. The purpose of this study was to investigate the importance of tumour and plasma concentrations of Foscan (mTHPC, meta-tetrahydroxyphenylchlorin) in relation to PDT effect. Both pharmacokinetic and tumour response studies were carried out in mice bearing s.c. RIF1 tumours. mTHPC was injected in 1 or 2 doses of 0.3 mg x kg-1. For distribution studies, 14C-labelled mTHPC was given 5 min to 48 hr before determination of plasma and tumour drug levels. Non-labelled sensitizer was used to determine the PDT efficacy for illumination at 5 min to 48 hr after drug administration. PDT efficacy was greatest for illumination at 1 to 3 hr, and for an interval of 48 hr there was no significant tumour-growth delay. In contrast, mTHPC tumour drug levels reached a maximum 6 hr after injection and remained high for 48 hr. A comparison of pharmacokinetics and response studies revealed no significant correlation between tumour mTHPC levels and tumour response. There was, however, a significant correlation between plasma drug levels and tumour response for time intervals of 1 to 48 hr. This association may imply that PDT protocols should use shorter drug-light intervals in combination with lower drug doses. This would increase safety and decrease the extent and duration of normal tissue photosensitization.
肿瘤中光敏剂的优先潴留一直是寻找新型光敏剂的主要目标之一，并决定了药物给药与光照之间间隔的临床试验设计。本研究的目的是探讨Foscan（mTHPC，间位四羟基苯基氯卟啉）的肿瘤和血浆浓度与光动力疗法（PDT）效果的关系。在皮下接种RIF1肿瘤的小鼠中进行了药代动力学和肿瘤反应研究。mTHPC以0.3 mg·kg-1的剂量分1或2次注射。对于分布研究，在测定血浆和肿瘤药物水平前5分钟至48小时给予14C标记的mTHPC。使用未标记的敏化剂来确定给药后5分钟至48小时光照的PDT疗效。光照1至3小时时PDT疗效最佳，间隔48小时则无明显的肿瘤生长延迟。相比之下，mTHPC肿瘤药物水平在注射后6小时达到峰值，并在48小时内保持较高水平。药代动力学和反应研究的比较显示，肿瘤mTHPC水平与肿瘤反应之间无显著相关性。然而，在1至48小时的时间间隔内，血浆药物水平与肿瘤反应之间存在显著相关性。这种关联可能意味着PDT方案应采用更短的药物-光照间隔并结合更低的药物剂量。这将提高安全性并减少正常组织光敏化的程度和持续时间。
