Henderson B W, Sitnik-Busch T M, Vaughan L A
Photodynamic Therapy Center, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
Photochem Photobiol. 1999 Jul;70(1):64-71.
The effects of systemic administration of the nitric oxide synthase (NOS) inhibitor NG-nitro-L-arginine (L-NNA) in combination with photodynamic therapy (PDT) on tumor response, tumor oxygenation and tumor and normal skin perfusion were studied in C3H mice bearing subcutaneous radiation-induced fibrosarcoma tumors. Photodynamic therapy was carried out using the photosensitizer Photofrin (5 mg/kg) in conjunction with a low fluence rate (30 mW/cm2) and a high fluence rate (150 mW/cm2) protocol at a total fluence of 100 J/cm2. Low fluence rate PDT produced approximately 15% tumor cures, a response not significantly altered by administration of 20 mg/kg L-NNA either 5 min before or after PDT. In contrast, high fluence rate PDT produced no tumor cures by itself, but addition of L-NNA either pre- or post-PDT resulted in approximately 30% and approximately 10% tumor cures, respectively. The L-NNA by itself tended to decrease tumor pO2 levels and perfusion, but statistically significant differences were reached only at one time point (1 h) with one of the oxygenation parameters measured (% values < 2 mm Hg). Photodynamic therapy by itself decreased tumor oxygenation and perfusion more significantly. Addition of L-NNA before PDT further potentiated this effect. The L-NNA exerted its most striking effects on the PDT response of the normal skin microvasculature. Low fluence rate PDT caused severe and lasting shut-down of skin microvascular perfusion. With high fluence rate PDT, skin perfusion was initially decreased but recovered to persistent normal levels within 1 h of treatment. Administration of L-NNA reversed this response, converting it to complete and lasting vascular shut-down identical to that achieved with low fluence rate PDT. This effect was somewhat L-NNA dose dependent but was still marked at a dose of 1 mg/kg. It occurred whether L-NNA was given before or after PDT. The L-NNA did not alter the long-term vascular response of skin to low fluence rate PDT. The ability of L-NNA to correspondingly improve tumor response and severely limit skin vascular perfusion following high fluence rate PDT, while providing no benefit for the low fluence rate protocol, suggests that vascular changes in the tumor surrounding normal tissue contribute to the enhanced tumor curability with adjuvant L-NNA treatment.
在携带皮下辐射诱导纤维肉瘤肿瘤的C3H小鼠中，研究了一氧化氮合酶（NOS）抑制剂NG-硝基-L-精氨酸（L-NNA）全身给药联合光动力疗法（PDT）对肿瘤反应、肿瘤氧合以及肿瘤和正常皮肤灌注的影响。光动力疗法使用光敏剂血卟啉（5mg/kg），分别按照低光通量率（30mW/cm²）和高光通量率（150mW/cm²）方案进行，总光通量为100J/cm²。低光通量率PDT产生了约15%的肿瘤治愈率，在PDT前5分钟或后给予20mg/kg L-NNA并未显著改变这一反应。相比之下，高光通量率PDT单独使用时未产生肿瘤治愈效果，但在PDT前或后添加L-NNA分别导致约30%和约10%的肿瘤治愈率。L-NNA单独使用时倾向于降低肿瘤pO₂水平和灌注，但仅在一个时间点（1小时）对所测量的一个氧合参数（%值<2mmHg）达到统计学显著差异。光动力疗法单独使用时更显著地降低了肿瘤氧合和灌注。在PDT前添加L-NNA进一步增强了这种效果。L-NNA对正常皮肤微血管的PDT反应产生了最显著的影响。低光通量率PDT导致皮肤微血管灌注严重且持久地关闭。对于高光通量率PDT，皮肤灌注最初降低，但在治疗后1小时内恢复到持续正常水平。给予L-NNA逆转了这种反应，使其转变为与低光通量率PDT相同的完全且持久的血管关闭。这种效应在一定程度上依赖于L-NNA的剂量，但在1mg/kg剂量时仍很明显。无论L-NNA在PDT之前还是之后给予，都会出现这种情况。L-NNA并未改变皮肤对低光通量率PDT的长期血管反应。L-NNA能够相应地改善高光通量率PDT后的肿瘤反应并严重限制皮肤血管灌注，而对低光通量率方案没有益处，这表明肿瘤周围正常组织中的血管变化有助于辅助L-NNA治疗提高肿瘤治愈率。
