Table 3.
Combinations of PDT and various therapeutic modalities in cancer treatment – a comprehensive summary.
| Drug or treatment modality | Outcome / Results |
|---|---|
| Chemotherapeutics and novel anticancer drugs | |
| Anthracyclines | Doxorubicin improves PDT-mediated tumor growth control in mice257 |
| Platinum compounds | Cisplatin potentiates antitumor activity of PDT in mice257 |
| Antimetabolites | Methotrexate enhances in vitro cytotoxicity of ALA-PDT by up-regulation of protoporphyrin IX production258 |
| Microtubule inhibitors | Vincristine administered prior or immediately after PDT improves its antitumor activity in mice259 |
| DNA methyltransferase inhibitors | 5-azadeoxycytidine prolongs survival of PDT-treated animals and improves tumor growth control260 |
| Proteasome inhibitors | Bortezomib enhances PDT-mediated ER-stress in cancer cells in vitro and significantly delays post-PDT tumor re-growth in mice48 |
| Radiotherapy | |
| Two-way enhancement of antitumor effects: PDT sensitizes cancer cells to radiotherapy261 and radiotherapy increases anticancer efficacy of PDT,262 prolonged tumor growth control induced by combined treatment212 | |
| Drugs modulating arachidonic acid cascade | |
| Cyclooxygenase-2 (COX-2) inhibitors | COX-2 inhibitors (such as NS-398109, nimesulid263 or celecoxib264) potentiate antitumor effects of PDT, possibly through indirect antiangiogenic effects |
| Lipoxygenase (LOX) inhibitors | MK-886, that also serves as a FLAP inhibitor, sensitizes tumor cells to PDT-mediated killing265 |
| Agents increasing photosensitizer accumulation in tumor cells | |
| Vitamin D | Increases 5-ALA-induced protoporphyrin IX accumulation and thus potentiates PDT cytotoxicity in vitro266 |
| Imatinib | Increases intracellular accumulation of 2nd generation PSs and thus potentiates PDT cytotoxicity in vitro and in vivo103 |
| Lipid lowering drugs | Lovastatin – a HMG-CoA reductase inhibitor improves in vitro LDL binding and Photofrin uptake by cancer cells267 |
| Salicylate and related drugs | Enhancement of PDT efficacy in vitro via increased PS uptake by tumor cells268 |
| Approaches increasing oxygen delivery to tumor cells | |
| Erythropoietin (EPO) | EPO improves chemotherapy-induced anemia and restores antitumor efficacy of PDT in mice269, however, EPO might also inhibit direct PDT-mediated cytotoxicity towards certain cancer cells270 |
| Hyperbaric oxygen | Increased antitumor effects of PDT in mice271 and in advanced pleural tumors in humans272 |
| Hyperthermia | In various treatment regimens, hyperthermia potentiates antitumor efficacy of PDT in vitro and in animal models.273 Short time interval between these two treatment modalities might increase normal tissue injury via vascular effects274 |
| Targeting cytoprotective mechanisms and increasing of radical formation in cancer cells | |
| Disruption of heme degradation pathway | Targeting of HO-1 with selective inhibitors107, siRNA275 as well as a siRNA-mediated knockdown of ferrochelatase275 or chelatation of iron ions276 potentiate antitumor effects of PDT |
| Inhibition of superoxide dismutase | 2-methoxyestradiol, a natural SOD inhibitor enhances PDT cytotoxicity in vitro and improves antitumor effects of PDT in mice41 |
| NO synthase inhibition | Improved tumor response to PDT in mice108 |
| HSP90 modulation | Interference with HSP90 client proteins binding using a geldanamycin derivative improves responsiveness to PDT both in vitro and in vivo106 |
| Lowering cellular glutathione content | Depleting GSH levels in tumor cells using buthionine sulfoximine significantly enhances PDT efficacy in vitro and in vivo277 |
| Vitamin E and its analogues | α-tocopherol-mediated radical production enhances PDT toxicity in vitro and in vivo278 |
| Targeting of tumor vasculature | |
| Antiangiogenic treatment | Anti-VEGF279 or anti-VEGFR280 monoclonal antibodies, matrix metalloproteinase inhibitor (prinomastat)281, TNP- 470282 and other anti-angiogenic agents110,283 as well as adenovirus-driven IL-12 expression284 potentiate antitumor effects of PDT in mice |
| Apoptosis promotion or G1 cell cycle inhibition in PDT-treated cells | |
| Bcl-2 antagonist synergizes with PDT in in vitro cytotoxicity285 | |
| Ursodeoxycholic acid sensitizes mitochondrial membranes in tumor cells to PDT-mediated damage286 | |
| A ceramide analogue delays tumor re-growth post PDT in mice287 | |
| Rapamycin (a mTOR inhibitor) delivered post PDT enhances its in vitro cytotoxicity288 | |
| Other approaches | |
| Combinations of two different photosensitizers |
5-ALA- and low dose Photofrin-PDT show enhanced antitumor efficacy in vitro and in vivo with no risk of prolonged skin photosensitivity113 |
| BPD- and benzothiazine-PDT synergize in antitumor activity in vitro and in vivo289 | |
| Hypoxia-activated bioreductive drugs | Improved tumor response to PDT in mice exposed to mitomycin C290 |
Abbreviations used: 5-ALA, 5-aminolaevulinic acid; BPD, benzoporphyrin derivative; COX, cyclooxygenase; EPO, erythropoietin; FLAP, 5-lipoxygenase activating protein; GSH, glutathione; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; HO-1, heme oxygenase-1; HSP, heat shock protein; LOX, lipoxygenase; mTOR, mammalian target of rapamycin; PS, photosensitizer; SOD, superoxide dismutase; VEGFR, vascular endothelial growth factor receptor.