Table 1:
PDT: preclinical studies.
| Author | Year | Animal model | Tumor model | PS used | Interval between PS injection and illumination (h) | Energy | Type of study | Results |
|---|---|---|---|---|---|---|---|---|
| Tochner | 1985 | Mice (n=68) | Ovarian: embryonal ovarian carcinoma | Photofrin°: 1th G | 2h and 15d | 9.6 J/cm2 | Phase III | Toxicity: The treatment resulted in death in 5 mice (1 only autopsy: perforation of small bowel) |
| Tumour response: 26 of 29 mice (mice that survived beyond 72 h after treatment with both Photofrin° and laser light) had a marked reduction in abdominal girth. One half of these returned to weights similar to those of normal mice that had no tumor transplant. | ||||||||
| Survival: | ||||||||
| PDT group: 17/20 (85 %) survival at 25 days. These were disease free at 11 months. | ||||||||
| All mice not receiving PDT treatment died between days 20 and 23. | ||||||||
| Tochner | 1991 | Canine (n=13) | Non-tumoral | Photofrin°: 1th G | 2 h | 0.57–0.74 J/cm2 | Phase I | All animals tolerated the treatment without significant morbidity. |
| Histopathology: Liver consistently showed hemosiderin-like deposits mainly in the periportal parenchymal cells+a 50 % incidence of mild inflammatory peritoneal response. | ||||||||
| Perry | 1991 | Mice (n=40) | Sarcoma: MCA-207 | Photofrin°: 1th G | 24 h | 2.08 J/cm2 | Phase I | Tumor PS concentration: no difference between IV and IP administration. IP administration resulted in longer elimination half-time (113.6 h vs 60.6 h) |
| Toxicity: Survival data of non-tumor bearing. Although there were survivors in the IP sensitizer group the difference was not statistically significant | ||||||||
| Morlet | 1995 | mice | Colon: HT 29 | mTHPC: 2nd G | 24–72 h | 10 J/cm2 | Phase II | Amount of m-THPC in tissues by high performance liquid chromatography (HPLC) and spectrofluorometry: |
|
mTHPC 0.8 and 1.6 mg/kg: HPLC and spectrofluorometric measurements: ratios (tumor to skin and tumor to muscle) decreased between 12 and 72 h after injection (of 0.8 and 1.6 mg/kg m-THPC) → indicating that tumour-selectivity decreases with time | ||||||||
| Phototoxicity: slight erythema was observed with 10 J/cm2 2 h after irradiation. With 30 J/cm2, skin was burnt and required 7 days to heal | ||||||||
| Tumour growth: | ||||||||
| – laser performed 24 h after m-THPC injection: a decrease in the tumor growth (−40 %) index was noted only for mice injected with 1.6 mg/kg (p<0.01) | ||||||||
| – laser performed 72 h after m-THPC injection: no significant difference in the tumour growth index | ||||||||
| Veenhuizen | 1997 | Rat | Colon: CC531 | mTHPC: 2nd G | IV: 24 and 72 hIP: 4 and 24 h | 4–24 h: 6 or 10 J/cm272 h: 25–50 J/cm2 | Phase II | mTHPC distribution: The tumour/normal tissue ratios were more than 5 for all tissues tested at 24 h after ip. administration, and more than 10 for all tissues except pancreas, fat and diaphragm |
| Regrowth times (single-tumour model only): Significant delay in tumour regrowth was achieved for 6 J/cm2 at 24 h after IV, or at 4 h after IP mTHPC (p=0.019 and 0.045, respectively). | ||||||||
| Optimal illumination time: Repeated administration of mTHPC (2*0.15 mg/kg−1) and illumination (2*6 or 10 J/cm2) with a 1 week interval also failed to improve tumour response | ||||||||
| Griffin | 2001 | Canine (n=13) | Non-tumoral | Lu-Tex: 1th G | 3 h | 0.5–2.0 J/cm2 | Phase I | All of the dogs tolerated IP PDT without major acute or late clinical effects. All treated dogs and one control dog showed transient elevations in hepatic enzyme |
| Song | 2007 | Rat (n=344) | Ovarian: NuTu-19 | HMME: 2rd G | 3 h | 50 J/cm2 | Phase III | Survival: PDT prolonged survival (p=0.008) |
| At the end of the study: | ||||||||
| – treatment group: the median follow-up time of 45 days (95 % CI, 1.17–88.83 days), the survival rate was 33.3 % | ||||||||
| – control groups: the median follow-up was 15 days (95 % CI, 6.68–23.32 days) and 19 days (95 % CI, 13.16–24.84 days) (surgery alone and surgery+laser without PS) | ||||||||
| Ascencio | 2008 | Rat (n=22) | Ovarian: NuTu-19 | HAL: 2nd G | 4 h | 45 J/cm2 | Phase II | Necrosis and normalized fluorescence intensities (ratio between the fluorescence intensity before and after illumination (percentage)). Direct linear correlation between normalized fluorescence intensity and necrosis (R2=0.89) |
| Ascencio | 2008 | Rat (n=36) | Ovarian: NuTu-19 | HAL: 2nd G | 4 h | Fractioned illumination: 30 J cm2Linear illumination: 45 J cm2 | Phase II | Necrosis: was superior with fractionated illumination compared to continuous illumination (3.67±0.70 vs. 3.10±0.94) (p<0.05) |
| Estevez | 2010 | Rat (n=60) | Ovarian: NuTu-19 | HAL: 2nd G | 4 h | Fractioned illumination: 30 J cm2Linear illumination: 45 and 30 J cm2 | Phase II | Necrosis: Fractionated illumination is more efficient than continuous illumination at 45 J cm−2 (213±113 µm vs 154±133 µm) (p<0.05) and than continuous illumination at 30 J cm2 (213±113 µm vs 171±155 µm) (pπ.05) |
| Kishi | 2010 | Mice | Gastric: MKN-4 | Talaporfin: 1th G | 2–8 h | 2, 5, and 10 J/cm2 | Phase II | Talaporfin concentration: Fluorescent intensity ratio gradually decreased over time compared to the ratio observed at 2 h |
| – in the peritoneal tumors: 78 % at 4 h/48 % at 8 h | ||||||||
| – in liver: 79 % at 4 h/31 % at 8 h | ||||||||
| – in small intestine: 36 % at 4 h/24 % at 8 h | ||||||||
| Necrosis: Dependent on the time interval between laser treatment and talaporfin administration at all laser doses (2 J/cm2, p<0.0001; 5 J/cm2, p=0.022; 10 J/cm2, p<0.0001), but they were independent of the laser dose at both timestreatment conditions recommended: 2 J/cm2 laser dose and a 4-h interval | ||||||||
| Raue | 2010 | Rat (n=90) | Colon DHD/K12/TRb | HAL: 2nd G | 6 h | 3.0 W. | Phase II | Tumour weight: CRS+HIPEC → lesser than in all other treatment groups (p=0.09) |
| Experimental Peritoneal Carcinosis Index (ePCI): CRS+HIPEC → 4 (0–14), the lowest ePCI count (p=0.03) | ||||||||
| Only additional HIPEC therapy with mitomycin showed a significant tumour reduction | ||||||||
| Mroz | 2011 | mice | Colon: CT26 | BB4-Cremophor: 3rd G | 24 h | 100 J/cm2 | Phase III | Bioluminescence: BB4-Cremophor significantly suppressed tumor growth compared with control treatmentSurvival: BB4-Cremophor-mediated PDT with white light leads to significant survival advantage |
| Necrosis and Apoptosis: Necrosis rather than apoptosis was the main mode of cell death (TUNEL: no apoptotic cell) | ||||||||
| Hino | 2013 | Mouse | Gastric: MKN-45 | HAL: 2nd G | 5 h | 4.5 J/cm2 | Phase II | Necrosis: Necrotic areas significantly larger in the treated group |
| Violet and green LEDs: Equally effective (p=0.368), with both significantly more effective than the red LED | ||||||||
| Guyon | 2014 | Rat (n=42) | Ovarian: NuTu-19 | HAL: 2nd G | 4–8 h | 0.8, 5, 10, or 20 J/cm2 | Phase I | Toxicity: Rhabdomyolysis, intestinal necrosis and liver function test anomalies. The highest delta between basal PPIX content and PPIX content after HAL administration was found for the liver (X27), the lungs (X16) and tumor nodules (X14). HAL PDT lacked specificity |
| Azais | 2016 | Rat (n=18) | Ovarian: NuTu-19 | Porph-s-FA: 3rd G | No illumination | No illumination | Phase I | Immunohistochemistry techniques: |
| – ovary, liver, and tumor tissue showed FRα positive cell contingents | ||||||||
| – peritoneum, small intestine, colon, kidney were FRα – negative tissue | ||||||||
| Confocal microscopy: cytoplasmic red endocytosis vesicles are correlated to FRα tissue expression colon, small intestine, kidney, and peritoneum: no fluorescence Ovary | ||||||||
| Tissue quantification of Porph-s-FA: the mean tumor-to-normal tissue ratio: 9.6 | ||||||||
| Yokoyama | 2016 | Rat | Ovarian: DISS | Methyl-ALA+ CA: 3rd G | 3 h | 90 J/cm2 | Phase III | Survival: |
| Mean survival time: | ||||||||
| – DS alone: 35.5 days | ||||||||
| – DS+methyl-ALA-PDT:46.3 days | ||||||||
| – DS+methyl-ALA-PDT+CA: 52.5 days | ||||||||
| – DS+methyl-ALA: longer survival time compared to DS alone (p=0.08) | ||||||||
| – DS+methyl-ALA-PDT+CA: significantly longer survival time compared to DS alone (p<0.005) | ||||||||
| Azais | 2017 | Rat | Ovarian: NuTu-19 (and SKOV-3 in vitro) n=18 | Porph-s-FA: 3rd G | No illumination | No illumination | Phase I | Tissue quantification of Porph-s-FA: The mean tumor-to-normal tissue ratio: 9.6Fluorescence measurement: carcinomatosis=higher fluorescence than liver and peritoneum |
| Kato | 2017 | Mice | Pancreas: AsPC1/luc | Mal3-chlorin vs talaporphin: 3rd G vs 1th G | 4 h and 7 d | 13.9 J/cm2 | Phase II | Bioluminescence imaging: Mal3-chlorin significantly suppressed tumor growth compared with control treatment (p=0.036) and tended to suppress it more than PDT with talaporfin (p=0.074) |
| Ascite: Mal3-chlorin tend to inhibit the volume of ascites compared to mice in the control and PDT with talaporfin group (p=0.066 and p=0.159, respectively) | ||||||||
| Apoptosis: Mal3-chlorin significantly increased apoptosis indices compared with control treatment or PDT with talaporfin |
Porph-s-FA, 5-(4-Carboxyphenyl)-10,15,20-triphenylporphyrin (Porph) and {N-{2-[2-(2-aminoethoxy)ethoxy]ethyl}folic acid}-4- carboxyphenylporphyrin; Lu-Tex, Motexafin lutetium; HAL, 5-aminolevulinic acid; PPIX, protoporphyrin IX; Mal3-chlorin, maltotriose-conjugated chlorin, (5,10,15,20-tetrakis-[4-(β-D-maltotriosylthio)-2,3,5,6-tetrafluorophenyl]-2,3-[methano-(N-methyl)iminomethano]chlorin); BB4-Cremophor, N-methylpyrrolidinium-fullerene formulated in Cremophor-EL micelles; IP, intraperitoneal; IV, intravenous; HMME, Hematoporphyrin monomethyl ether; mTHPC, meta-tetrahydroxyphenylchlorin; methyl-ALA + CA, 5-aminolevulinic acid methyl ester hydrochloride and clofibric acid