Mono-L-aspartyl chlorin e6 (NPe6) and hematoporphyrin derivative (HpD) in photodynamic therapy administered to a human cholangiocarcinoma model.
BACKGROUND
Despite their relatively localized nature, the therapy for surgically unresectable cholangiocarcinomas has been largely unsuccessful. Photodynamic therapy is a promising technique for both curative and palliative treatment of this malignancy. The effectiveness of a potential new photosensitizer, mono-l-aspartyl chlorin e6 (NPe6), was compared with that of a traditional drug, hematoporphyrin derivative (HpD), in photodynamic therapy administered to a human cholangiocarcinoma model.


METHODS
An established cholangiocarcinoma cell line was inoculated subcutaneously in the left back of male nude mice age 8 weeks. After a predetermined tumor size was reached, the mice were randomly assigned to either a control group or an experimental group. Experimental tumor-bearing mice received either HpD (5 mg/kg or 10 mg/kg) or NPe6 (2 mg/kg, 5 mg/kg, or 8 mg/kg) followed by photoradiation. HpD and NPe6 were administered intraperitoneally at 24 and 2 hours, respectively, prior to light exposure. Photoradiation was conducted using a xenon-mercury arc lamp with a 405-650 nm filter at a light flux of 80 J/cm2. Tumor response was assessed by serial tumor volume measurements.


RESULTS
Control mice showed an estimated mean tumor volume doubling rate of 9.0 days. Triaxial tumor measurements correlated well with autopsy measurements (correlation coefficient = 0.9). Overall differences in tumor volume reduction were detected (P < 0.001) among the three groups: HpD, NPe6, and controls (photoradiation only, HpD only, or NPe6 only). The degree of tumor volume reduction was superior for dosages of NPe6 compared with all dosages of HpD (P < 0.05). Although a dose effect was detected (P < 0.05) for HpD and separately for NPe6, a consistent dose-response relationship was not observed for either. Inhibition of tumor regrowth was better for NPe6 compared with HpD. The depth of tissue injury was significantly increased (P < 0.05), by 67%, for 5-8 mg/kg of NPe6 compared with 5-10 mg/kg of HpD. The duration of cutaneous photosensitization was also decreased for NPe6 compared with HpD.


CONCLUSIONS
Photodynamic therapy with HpD or NPe6 was effective inducing tumor regression in the cholangiocarcinoma model in this study. At the dosages studied, NPe6 appeared to induce greater tumor regression than HpD, with decreased tumor regrowth and duration of cutaneous photosensitization.
Wong Kee Song
L M
LM
Division of Gastroenterology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Wang
K K
KK
Zinsmeister
A R
AR
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D017324:Hematoporphyrin Derivative / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006414:Hematoporphyrin Photoradiation / Q000009:adverse effects; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D008628:Mercury; D051379:Mice; D008819:Mice, Nude; D010166:Palliative Care; D010778:Photochemotherapy / Q000009:adverse effects; D010787:Photosensitivity Disorders / Q000209:etiology / Q000517:prevention & control; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011166:Porphyrins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011897:Random Allocation; D012074:Remission Induction; D012867:Skin / Q000187:drug effects; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000473:pathology; D014978:Xenon
D000970:Antineoplastic Agents; D017319:Photosensitizing Agents; D011166:Porphyrins; D014978:Xenon; D017324:Hematoporphyrin Derivative; D008628:Mercury; C053434:Talaporfin