Hua Z, Gibson S L, Foster T H, Hilf R
Department of Biochemistry, University of Rochester School of Medicine and Dentistry, New York 14642, USA.
Cancer Res. 1995 Apr 15;55(8):1723-31.
We examined the effectiveness of systemic administration of delta-aminolevulinic acid (delta-ALA) to induce endogenous protoporphyrin as a regimen for use in photodynamic therapy (PDT) of transplanted R3230AC rat mammary adenocarcinomas in vivo. Levels of porphyrins synthesized in various tissues after systemic administration of delta-ALA differed, with their accumulation in tumor tissue being dependent on both the dose and the time after delta-ALA administration. Tumor, liver, and intestine contained greater than 3.0 micrograms porphyrin/g tissue at 3 h after delta-ALA injection, whereas porphyrin levels in rat skin and muscle at that time were an order of magnitude lower. Analysis of tissue by HPLC revealed that the predominant porphyrin synthesized in tumors was protoporphyrin IX, whereas in liver, 18% of the total porphyrin detected was protoporphyrin IX, and in muscle, it was undetectable. Time-dependent studies of the uptake of 14C label from delta-ALA into the various tissues were not predictive of either the total amount of porphyrin or which porphyrin species would be present at 3 h after delta-ALA injection. Additionally, no simple relationship was apparent between the activities of certain selected enzymes involved in heme biosynthesis and the concentrations of porphyrins in the different tissues. High levels of tumor protoporphyrin IX were sustained by administration of two sequential doses of delta-ALA, at 3.0 and 1.5 h prior to irradiation. Using these treatment conditions, we inhibited R3230AC growth to an extent that was comparable to that obtained for Photofrin-induced PDT. High energy phosphate metabolism, measured by nuclear magnetic resonance spectroscopy in vivo, was dramatically impaired after delta-ALA-based PDT, with tumor ATP levels reduced to near zero by 4 h after irradiation. Our results demonstrated that delta-ALA-based PDT may be an alternative to current treatment protocols that use exogenously administered photosensitizers.
我们研究了全身给予δ-氨基乙酰丙酸（δ-ALA）以诱导内源性原卟啉作为一种方案用于体内移植的R3230AC大鼠乳腺腺癌光动力疗法（PDT）的有效性。全身给予δ-ALA后，各种组织中合成的卟啉水平有所不同，其在肿瘤组织中的积累取决于δ-ALA给药后的剂量和时间。在注射δ-ALA后3小时，肿瘤、肝脏和肠道中卟啉含量大于3.0微克/克组织，而此时大鼠皮肤和肌肉中的卟啉水平低一个数量级。通过高效液相色谱法对组织进行分析表明，肿瘤中合成的主要卟啉是原卟啉IX，而在肝脏中，检测到的总卟啉中有18%是原卟啉IX，在肌肉中则无法检测到。对从δ-ALA中摄取的14C标记物进入各种组织的时间依赖性研究并不能预测卟啉的总量或在注射δ-ALA后3小时会存在哪种卟啉种类。此外，参与血红素生物合成的某些选定酶的活性与不同组织中卟啉浓度之间没有明显的简单关系。在照射前3.0小时和1.5小时连续给予两剂δ-ALA，可维持肿瘤中原卟啉IX的高水平。使用这些治疗条件，我们将R3230AC的生长抑制到与Photofrin诱导的PDT相当的程度。通过体内核磁共振波谱法测量，基于δ-ALA的PDT后高能磷酸代谢受到显著损害，照射后4小时肿瘤ATP水平降至接近零。我们的结果表明，基于δ-ALA的PDT可能是当前使用外源性给予光敏剂的治疗方案的替代方法。
