Bremachlorin® is a second-generation photosensitizer that is currently undergoing careful scientific evaluation in the Netherlands. The agent is known as Radachlorin® in Russia, where it is clinically approved for various skin and cancer treatments. Clinical studies in Russia are ongoing. At this writing, a total of 15 clinical studies have been completed, of which 10 were approved by the official scientific authorities in Russia. Preclinical studies are now under way in the Netherlands with a goal toward achieving clinical acceptance in the European Union.
Bremachlorin is taken up easily by cancer cells and can accumulate rapidly (within 30 minutes to 5 hours) in malignant tutors. It is also retained very well within the tumor while being excreted fairly quickly by normal tissues. It has been proposed that Bremachlorin’s high level of therapeutic efficacy as a component of PDT for cancer is related to the ability to readily penetrate biological membranes (thus entering living cells with ease) as well as to a greatly increased accumulation in tumor tissues compared to surrounding healthy tissues.
The mechanism of Bremachlorin’s therapeutic action is only apparent when exciting the preparation by light, especially with a wavelength of 660-665 nm, which allows for deeper tissue penetration during the light treatment. Photoactivation of the Bremachlorin results in an effective generation of highly cytotoxic particles, such as singlet oxygen, within the malignant tumor. The quantum yield of such oxygen radicals is 75% to 96% depending on the physical and chemical properties of the test medium.
Bremachlorin contains three components (Chlorin e6, Chlorin p6, Purpurin 5) that target different aspects of cancer biology: (1) Vascular damage, or interfering with the growth of new blood vessels that in turn enable tumors to grow; (2) damage to the cancer cell’s membranes and cell signaling system, along with increased recognition by the body’s anti-cancer immune defenses; and (3) damage to the cancer cell’s internal structures, in particular the mitochondria and DNA.
Thus, the three components in Bremachlorin® result in a unique, multi-faceted tumor-killing potential. The third component, Purpurin 5, is the most critical in terms of finally killing the tumor. Because this compound shows a high degree of chemical instability, it must be combined with the two chlorin compounds in order to become stable and successfully delivered to the tumor. The three compounds explain Bremachlorin’s success as both a therapeutic and a diagnostic agent. When used in fluorescent diagnosis, this trio cause the entire tumor to glow or fluoresce. First the entire tumor fluoresces, then individual cells, and then the organelles.
Researchers from Leiden University Medical Center and Erasmus University Medical Center (Rotterdam, the Netherlands) have shown that Bremachlorin displays a more lasting tumor-killing potential compared to Chlorin e6 alone. Bremachlorin’s ability to accumulate preferentially in tumors may allow for selective targeting of those tumors. The researchers propose that such research can be used to help define an optimal treatment protocol for Bremachlorin-PDT. These research findings were reported in the January 2014 Journal of Biomedical Optics and also in the March 2014 issue of Lasers in Surgery and Medicine.
Cancers of the skin, bladder, brain, breast and lung are just a few of the cancers being considered for future studies of Bremachlorin-PDT. At this time, various Bremachlorin doses and light exposures are being explored in order to determine the optimal protocols for Bremachlorin-PDT as primary and adjuvant treatments for malignant disease. As a primary treatment, this approach has been especially effective in the elimination of small tumors—and in particular, more superficial tumors or those readily exposed to laser or other light sources.
Following the light treatment, the following therapeutic effects have been attributed to Bremachlorin-PDT:
• greatly obstructed blood flow to the tumor
• accelerated destruction of the tumor (necrosis)
• increased activation of anti-cancer immune mechanisms
When used as an adjuvant treatment, Bremachlorin-PDT could be useful in the following situations:
• to eliminate residual tumor following surgical debulking (i.e., surgical removal of the bulk of the tumor)
• to help prevent the formation of metastases following surgery
• to lower the dose of radiotherapy needed for treating larger, inoperable tumors
• to eliminate cancer cells that have become resistant to chemotherapy and radiation treatments. It may be used to.
Bremachlorin-PDT can be used before, during or after surgery. Chemotherapeutic and radiation treatments can enhance the effect of Bremachlorin-PDT. When combined with these treatments, however, the Bremachlorin infusion must precede chemotherapy and follow radiation treatment.
Following intravenous administration of Bremachlorin®, there is a risk of skin hypersensitivity to therapeutic doses of irradiation during and after light treatment (photosensitivity). Symptoms of skin photosensitivity may include the skin becoming red, irritated, swollen, and sore, sometimes with small blisters. Such reactions are typically only seen with extended exposure to sunlight following PDT.
Once the Bremachlorin preparation is administered, the patient must avoid prolonged exposure (longer than 30 minutes) to direct sunlight. In the summertime, such avoidance should be practiced for two consecutive days after the treatment; in wintertime, avoidance should be practiced for 24 hours after the treatment. Bremachlorin is contraindicated for anyone with a known hypersensitivity to any ingredient of the drug.
No test of the preparation has been conducted with pregnant women. Therefore, as with other medicinal preparations, Bremachlorin should not be administered during pregnancy. The most “high risk” period may be during the first three months of gestation unless the physician is convinced that the expected benefit for the mother’s health will be greater than a potential risk to the fetus.
Kleinovink JW, van Driel PB, Snoeks TJ, Prokopi N, Fransen MF, Javier Cruz L, Mezzanotte L, Chan A, Lowik CW, Ossendorp F. Combination of photodynamic therapy and specific immunotherapy efficiently eradicates established tumors. Clin Cancer Res. 2015 Nov 6. [Epub ahead of print]
van Leeuwen-van Zaane F, van Driel PB, Gamm UA, Snoeks TJ, de Bruijn HS, van der Ploeg-van den Heuvel A, Löwik CW, Sterenborg HJ, Amelink A, Robinson DJ. Microscopic analysis of the localization of two chlorin-based photosensitizers in OSC19 tumors in the mouse oral cavity. Lasers Surg Med. 2014 Mar;46(3):224-34.
van Leeuwen-van Zaane F, Gamm UA, van Driel PB, Snoeks TJ, de Bruijn HS, van der Ploeg-van den Heuvel A, Sterenborg HJ, Löwik CW, Amelink A, Robinson DJ. Intrinsic photosensitizer fluorescence measured using multi-diameter single-fiber spectroscopy in vivo. J Biomed Opt. 2014 Jan;19(1):15010.
Fekrazad R, Zare H, Mohammadi Sepahvand S, Morsali P. The effect of antimicrobial photodynamic therapy with radachlorin® on Staphylococcus aureus and Escherichia coli: an in vitro study. J Lasers Med Sci. 2014 Spring;5(2):82-5.
Kochneva EV, Filonenko EV, Vakulovskaya EG, Scherbakova EG, Seliverstov OV, Markichev NA, Reshetnickov AV. Photosensitizer Radachlorin®: Skin cancer PDT phase II clinical trials. Photodiagnosis Photodyn Ther. 2010 Dec;7(4):258-67.
Akopov A, Rusanov A, Gerasin A, Kazakov N, Urtenova M, Chistyakov I. Preoperative endobronchial photodynamic therapy improves resectability in initially irresectable (inoperable) locally advanced non small cell lung cancer. Photodiagnosis Photodyn Ther. 2014 Sep;11(3):259-64.
Akopov AL, Rusanov AA, Chistiakov IV, Urtenova MA, Kazakov NV, Gerasin AV, Papaian GV. Application of photodynamic therapy to reduce the amount of resection for non-small cell lung cancer. [Article in Russian] Vopr Onkol. 2013;59(6):740-4.
Ji W, Yoo JW, Bae EK, Lee JH, Choi CM. The effect of Radachlorin® PDT in advanced NSCLC: a pilot study. Photodiagnosis Photodyn Ther. 2013 May;10(2):120-6.
Lee JY, Diaz RR, Cho KS, Lim MS, Chung JS, Kim WT, Ham WS, Choi YD. Efficacy and safety of photodynamic therapy for recurrent, high grade nonmuscle invasive bladder cancer refractory or intolerant to bacille Calmette-Guérin immunotherapy. J Urol. 2013 Oct;190(4):1192-9.
Filonenko EV1, Sokolov VV, Chissov VI, Lukyanets EA, Vorozhtsov GN. Photodynamic therapy of early esophageal cancer. Photodiagnosis Photodyn Ther. 2008 Sep;5(3):187-90
Biswas R1, Moon JH, Ahn JC. Chlorin e6 Derivative Radachlorin Mainly Accumulates in Mitochondria, Lysosome and Endoplasmic Reticulum and Shows High Affinity towards Tumors in Nude Mice in Photodynamic Therapy. Photochem Photobiol. 2014 Mar 26. doi: 10.1111/php.12273. [Epub ahead of print]