In this review we discuss the effect of photodynamic treatment (PDT) of solid tumors on the immune response. The effect on both the innate and adapted immune response is discussed. We have summarized ...the evidence that PDT causes or enhances an anti-tumor response. PDT is a local treatment in which the treated tumor remains in situ while the immune system is only locally affected and still functional in contrast with e.g. after systemic chemotherapy. We conclude that PDT of cancer is a way of in situ vaccination to induce a systemic anti-tumor response. In general, immune cells are found in the tumor stroma, separated from tumor cells by extracellular matrix and basal membrane-like structures. We hypothesize that PDT destroys the structure of a tumor, thereby enabling direct interaction between immune cells and tumor cells resulting in the systemic anti-tumor immune response.
The prognosis for patients with liver metastases from colorectal carcinoma is limited because of the low number of patients who are eligible for curative hepatic resection. In this phase I study, 31 ...liver metastases in 24 patients with nonresectable metastases from colorectal carcinoma were treated with photodynamic therapy (PDT).
The photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)bacteriochlorin (mTHPBC) was intravenously administered in a dose of .6 mg/kg (n = 12) or .3 mg/kg (n = 12). After 120 hours (n = 18) or 48 hours (n = 6), tumors were illuminated for 300 to 600 seconds through percutaneously inserted optical fibers with a light dose of 60 J/cm of diffuser (740 nm).
Tumor necrosis at 1 month after PDT was achieved in all treated lesions. Laser treatment was associated with mild pain (n = 8) and transient subclinical hepatotoxicity (n = 21). In one patient, PDT damage to the pancreas was inflicted, and in another patient, PDT damage of the skin occurred, but no serious clinical complications from PDT were reported. Administration of .6 mg/kg of mTHPBC led to transient phlebitis in 10 patients, and 3 patients experienced mild skin phototoxicity after excess light exposure.
Colorectal liver metastases that are ineligible for resection can be safely and effectively treated with interstitial mTHPBC-based PDT.
We have investigated tumor immunological effects of photodynamic therapy (PDT) of liver metastases. Livers of Wag/Rij rats were inoculated with three tumors of a syngeneic rat colon carcinoma cell ...line, CC531. One tumor in each rat was illuminated, with or without previous administration of the photosensitizer metatetrahydroxyphenylchlorin (mTHPC). PDT was effective in causing necrosis of tumors, but it did not affect the growth rate of nearby, nonilluminated tumors in the liver. Immunological staining of tumors showed natural killer (NK) cells to be significantly lower in PDT-treated tumors than in control tumors (P < 0.05). T cells in PDT-treated tumors and in their margins were lower than in tumors that received only sensitizer or only illumination (P = 0.015) at day 2 after treatment but reappeared at the tumor margins from day 7 after treatment. For macrophages, a similar pattern was found. NK cells, T cells or macrophages in nonilluminated tumors in mTHPC-treated rats did not increase significantly when compared with tumors in rats without mTHPC treatment. These findings indicated that no antitumor effect of a systemic immune response was present, as measured by the effect of PDT on growth of distant tumors and the number of T lymphocytes, NK cells and macrophages in these tumors.
It has been proposed that the construction of a photosensitizer–polymer conjugate would lead to an increased selective retention of the drug in tumor tissue resulting in an enhancement of selective ...tumor destruction by light in photodynamic therapy. In this study the kinetics of a tetra-pegylated derivative of meta-tetra(hydroxyphenyl)chlorin (mTHPC–PEG) were compared with those of native meta-tetra(hydroxyphenyl)chlorin (mTHPC) in a rat liver tumor model. In addition, the time course of bioactivity of both drugs was studied in normal liver tissue. Pegylation of mTHPC resulted in a two-fold increase in the plasma half-life time, a five-fold decrease in liver uptake and an increase in the tumor selectivity at early time intervals after drug administration. However, although mTHPC concentrations in liver decrease rapidly with time, mTHPC–PEG liver concentrations increased as a function of time. This led to a loss of tumor selectivity at all but the earliest time points, whereas with mTHPC tumor selectivity increased with time. For both drugs the time course of bioactivity in the liver parallels drug concentration levels with extensive necrosis after irradiation of mTHPC–PEG-sensitized liver tissue up to drug–light intervals of 120 h. It is concluded that on balance mTHPC–PEG does not appear to show any benefits over native mTHPC for the treatment of liver tumors, as normal liver tissue accumulates the compound. However, pegylation is a potentially promising strategy with an increase in tumor selectivity and reduced liver uptake if accumulation in the liver can be prevented.
This paper describes the photodynamic characteristics of the new near-infrared photosensitizer 5,10,15,20-tetrakis(m-hydroxyphenyl)bacteriochlorin (mTHPBC or SQN400) in normal rat and mouse tissues. ...A rat liver model of photodynamic tissue necrosis was used to determine the in vivo action spectrum and the dose–response relationships of tissue destruction with drug and light doses. The effect of varying the light irradiance and the time interval between drug administration and light irradiation on the biological response was also measured in the rat liver model. Photobleaching of mTHPBC was measured and compared with that of its chlorin analog (mTHPC) in normal mouse skin and an implanted mouse colorectal tumor. The optimum wavelength for biological activation of mTHPBC in rat liver was 739 nm. mTHPBC was found to have a marked drug-dose threshold of around 0.6 mg kg−1 when liver tissue was irradiated 48 h after drug administration. Below this administered drug dose, irradiation, even at very high light doses, did not cause liver necrosis. At administered doses above the photodynamic threshold the effect of mTHPBC–PDT was directly proportional to the product of the drug and light doses. No difference in the extent of liver necrosis produced by mTHPBC was found on varying the light irradiance from 10 to 100 mW cm−2. The extent of liver necrosis was greatest when tissue was irradiated shortly after mTHPBC administration and necrosis was absent when irradiation was performed 72 h or later after drug administration, suggesting that the drug was rapidly cleared from the liver. In vivo photobleaching experiments in mice showed that the rate of bleaching of mTHPBC was approximately 20 times greater than that of mTHPC. It is argued that this greater rate of bleaching accounts for the higher photodynamic threshold and this could be exploited to enhance selective destruction of tissues which accumulate the photosensitizer.
ABSTRACT
We have investigated tumor immunological effects of photodynamic therapy (PDT) of liver metastases. Livers of Wag/Rij rats were inoculated with three tumors of a syngeneic rat colon ...carcinoma cell line, CC531. One tumor in each rat was illuminated, with or without previous administration of the photosensitizer metatetrahydroxyphenylchlorin (mTHPC). PDT was effective in causing necrosis of tumors, but it did not affect the growth rate of nearby, nonilluminated tumors in the liver. Immunological staining of tumors showed natural killer (NK) cells to be significantly lower in PDT‐treated tumors than in control tumors (P < 0.05). T cells in PDT‐treated tumors and in their margins were lower than in tumors that received only sensitizer or only illumination (P= 0.015) at day 2 after treatment but reappeared at the tumor margins from day 7 after treatment. For macrophages, a similar pattern was found. NK cells, T cells or macrophages in nonilluminated tumors in mTHPC‐treated rats did not increase significantly when compared with tumors in rats without mTHPC treatment. These findings indicated that no antitumor effect of a systemic immune response was present, as measured by the effect of PDT on growth of distant tumors and the number of T lymphocytes, NK cells and macrophages in these tumors.
The discussion on the use of bevacizumab is still ongoing and often doctors are deterred from using bevacizumab due to legal or political issues. Bevacizumab is an effective, safe and inexpensive ...treatment option for neovascular age-related macular degeneration (AMD), albeit unregistered for the disease. Therefore, in some countries ophthalmologists use the equally effective but expensive drugs ranibizumab and aflibercept. We describe the economic consequences of this dilemma surrounding AMD treatment from a societal perspective.
We modelled cost-effectiveness of treatment with ranibizumab (as-needed), aflibercept (bimonthly) and bevacizumab (as-needed). Effectiveness was estimated by systematic review and meta-analysis. The drug with the most favourable cost-effectiveness profile compared to bevacizumab was used for threshold analyses. First, we determined how much we overspend per injection. Second, we calculated the required effectiveness to justify the current price and the reasonable price for a drug leading to optimal vision. Finally, we estimated how much Europe overspends if bevacizumab is not first choice.
Bevacizumab treatment costs €27,087 per year, about €4,000 less than aflibercept and €6,000 less than ranibizumab. With similar effectiveness for all drugs as shown by meta-analysis, bevacizumab was the most cost-effective. Aflibercept was chosen for threshold analyses. Aflibercept costs €943 per injection, but we determined that the maximum price to be cost-effective is €533. Alternatively, at its current price, aflibercept should yield about twice the visual gain. Even when optimal vision can be achieved, the maximum price for any treatment is €37,453 per year. Most importantly, Europe overspends €335 million yearly on AMD treatment when choosing aflibercept over bevacizumab.
Bevacizumab is the most cost-effective treatment for AMD, yet is not the standard of care across Europe. The registered drugs ranibizumab and aflibercept lead to large overspending without additional health benefits. Health authorities should consider taking steps to implement bevacizumab into clinical practice as first choice.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
This paper describes the photodynamic characteristics of the new near‐infrared photosensitizer 5,10,15,20‐tetrakis(m‐hydroxyphenyl)bacteriochlorin (mTHPBC or SQN400) in normal rat and mouse ...tissues. A rat liver model of photodynamic tissue necrosis was used to determine the in vivo action spectrum and the dose–response relationships of tissue destruction with drug and light doses. The effect of varying the light irradiance and the time interval between drug administration and light irradiation on the biological response was also measured in the rat liver model. Photobleaching of mTHPBC was measured and compared with that of its chlorin analog (mTHPC) in normal mouse skin and an implanted mouse colorectal tumor. The optimum wavelength for biological activation of mTHPBC in rat liver was 739 nm. mTHPBC was found to have a marked drug‐dose threshold of around 0.6 mg kg−1 when liver tissue was irradiated 48 h after drug administration. Below this administered drug dose, irradiation, even at very high light doses, did not cause liver necrosis. At administered doses above the photodynamic threshold the effect of mTHPBC–PDT was directly proportional to the product of the drug and light doses. No difference in the extent of liver necrosis produced by mTHPBC was found on varying the light irradiance from 10 to 100 mW cm−2. The extent of liver necrosis was greatest when tissue was irradiated shortly after mTHPBC administration and necrosis was absent when irradiation was performed 72 h or later after drug administration, suggesting that the drug was rapidly cleared from the liver. In vivo photobleaching experiments in mice showed that the rate of bleaching of mTHPBC was approximately 20 times greater than that of mTHPC. It is argued that this greater rate of bleaching accounts for the higher photodynamic threshold and this could be exploited to enhance selective destruction of tissues which accumulate the photosensitizer.
ABSTRACT
It has been proposed that the construction of a photosensitizer–polymer conjugate would lead to an increased selective retention of the drug in tumor tissue resulting in an enhancement of ...selective tumor destruction by light in photodynamic therapy. In this study the kinetics of a tetra‐pegylated derivative of meta‐tetra(hydroxyphenyl)chlorin (mTHPC–PEG) were compared with those of native meta‐tetra(hydroxyphenyl)chlorin (mTHPC) in a rat liver tumor model. In addition, the time course of bioactivity of both drugs was studied in normal liver tissue. Pegylation of mTHPC resulted in a two‐fold increase in the plasma half‐life time, a five‐fold decrease in liver uptake and an increase in the tumor selectivity at early time intervals after drug administration. However, although mTHPC concentrations in liver decrease rapidly with time, mTHPC–PEG liver concentrations increased as a function of time. This led to a loss of tumor selectivity at all but the earliest time points, whereas with mTHPC tumor selectivity increased with time. For both drugs the time course of bioactivity in the liver parallels drug concentration levels with extensive necrosis after irradiation of mTHPC–PEG‐sensitized liver tissue up to drug–light intervals of 120 h. It is concluded that on balance mTHPC–PEG does not appear to show any benefits over native mTHPC for the treatment of liver tumors, as normal liver tissue accumulates the compound. However, pegylation is a potentially promising strategy with an increase in tumor selectivity and reduced liver uptake if accumulation in the liver can be prevented.
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