Efficient photodynamic therapy against drug-resistant prostate cancer using replication-deficient virus particles and talaporfin sodium

Lasers in Medical Science - To enhance the potency of photosensitizer, we developed a novel photosensitizer, Laserphyrin®-HVJ-E (L-HVJ-E), by incorporating talaporfin sodium...     

Suicide gene therapy for prostate cancer using a replication-deficient adenovirus containing the herpesvirus thymidine kinase gene

Current therapies for localized prostate cancer include radical prostatectomy, local radiation therapy, and cryoablation and are associated with a high rate of cure and acceptable morbidity. However, for men who have failed primary curative attempts or have metastatic disease, no effective therapy associated with acceptable morbidity exists. “Suicide” gene therapy delivered alone or in combination with other forms of treatment could potentially provide simultaneous efficacy against localized and systemic disease via the generation of cytotoxic activity and/or systemic immunity to the cancer. In this article we discuss our preclinical and clinical experience with a herpes-simplex-virus thymidine kinase/ganciclovir gene-therapy protocol for prostate cancer.     

Generation of effective vaccines against liver cancer by using photodynamic therapy

Preclinical studies have shown that photodynamic therapy (PDT) enhances immune responses. To examine the role of the direct effects of PDT in liver cancer with regard to enhancement of the antitumor response, we injected PDT-generated H22 liver cancer cell lysate (as a tumor vaccine) intradermally into Kunming mice. In the control group, the cell lysate was substituted with normal saline solution. A liver tumor model was established by the injection of H22 cell suspension. We found that the PDT-generated vaccine significantly increased the percentages of CD4⁺, CD8⁺, and CD19⁺ cells, inhibited tumor growth, and prolonged the survival time. Our findings suggest that PDT-generated vaccines can significantly enhance the antitumor immune response and may have the potential to be used as an adjuvant therapy clinically.     

Development of a practical animal model of photodynamic therapy using a high concentration of extracellular talaporfin sodium in interstitial fluid: influence of albumin animal species on myocardial cell photocytotoxicity in vitro

Photodynamic reaction-induced photocytotoxicity using talaporfin sodium is inhibited by serum proteins binding to talaporfin sodium. The serum albumin binding site for talaporfin sodium differs among animal species. To identify a practical animal therapeutic model, we studied the ability of human, canine, bovine, and porcine albumin to influence talaporfin sodium-induced photocytotoxicity in rat myocardial cells in vitro. Human, canine, bovine, and porcine serum albumins were used. The ratio of talaporfin sodium binding, which is strongly associated with photocytotoxicity, was measured by ultrafiltration with an albumin concentration of 0.5–20 mg/ml and 20 μg/ml talaporfin sodium to mimic interstitial fluid. Rat myocardial cell lethality was measured by the WST assay 2 h after samples were exposed to a radiant exposure of 20 J/cm² by a red diode laser (Optical Fuel?, Sony, Tokyo, Japan) with a wavelength of 663 nm. The binding ratio dependence on albumin concentration differed among the animal species. Bovine albumin exhibited the largest difference from human albumin, with a maximum difference of 31% at 2 mg/ml albumin. The cell lethality characteristic was similar between human and canine albumin. The cell lethality dependence on albumin was not in the same order as the binding ratio. Cell lethality was lowest for human albumin with higher albumin concentrations between 5 and 20 mg/ml. There were no significant differences in cell lethality between bovine and porcine albumin and between human and canine albumin. We suggest that the canine model may be a useful animal therapeutic model for evaluating photodynamic therapy using a high concentration of the photosensitizer in the extracellular space.     

Correction to: The clinical utility of prostate cancer heterogeneity using texture analysis of multiparametric MRI

International Urology and Nephrology - Unfortunately, in the original article one co-author’s name is missing. The co-author name and affiliation is given as follows.     

Photodynamic therapy: A new approach to prostate cancer

Photodynamic therapy (PDT) is based on the concept that light irradiation can change an inert substance into an active one. In urology, hematoporphyrin derivative (HpD) and Photofrin (Axcan Scandipharm Inc., Birmingham, AL) are used most commonly as photosensitizing agents predominantly for the treatment of transitional cell carcinoma of the bladder. To investigate the basics for PDT of prostate cancer, several studies were performed on the optical characteristics of prostate tissue and prostate carcinoma tissue in vitro and in vivo and on the penetration depths of different laser wavelengths. Initial experimental studies to treat prostate cancer with PDT using HpD were done on Dunning tumors in rats. Combined with interstitial applicators, photodynamic therapy seems to have a great potential in the treatment of prostate carcinoma. However, it is an experimental treatment and even a preliminary evaluation will be possible only after the conclusion of clinical studies with the corresponding long-term results.     

Vascular targeted photodynamic therapy with palladium-bacteriopheophorbide photosensitizer for recurrent prostate cancer following definitive radiation therapy: assessment of safety and treatment response

PURPOSE: Tookad is a novel intravascular photosensitizer. When activated by 763 nm light, it destroys tumors by damaging their blood supply. It then clears rapidly from the circulatory system. To our knowledge we report the first application of Tookad vascular targeted photodynamic therapy in humans. We assessed the safety, pharmacokinetics and preliminary treatment response as a salvage procedure after external beam radiation therapy. MATERIALS AND METHODS: Patients received escalating drug doses of 0.1 to 2 mg/kg at a fixed light dose of 100 J/cm or escalated light doses of 230 and 360 J/cm at the 2 mg/kg dose. Four optical fibers were placed transperineally in the prostate, including 2 for light delivery and 2 for light dosimetry. Treatment response was assessed primarily by hypovascular lesion formation on contrast enhanced magnetic resonance imaging and transrectal ultrasound guided biopsies targeting areas of lesion formation and secondarily by serum prostate specific antigen changes. RESULTS: Tookad vascular targeted photodynamic therapy was technically feasible. The plasma drug concentration was negligible by 2 hours after infusion. In the drug escalation arm 3 of 6 patients responded, as seen on magnetic resonance imaging, including 1 at 1 mg/kg and 2 at 2 mg/kg. The light dose escalation demonstrated an increasing volume of effect with 2 of 3 patients in the first light escalation cohort responding and all 6 responding at the highest light dose with lesions encompassing up to 70% of the peripheral zone. There were no serious adverse events, and continence and potency were maintained. CONCLUSIONS: Tookad vascular targeted photodynamic therapy salvage therapy is safe and well tolerated. Lesion formation is strongly drug and light dose dependent. Early histological and magnetic resonance imaging responses highlight the clinical potential of Tookad vascular targeted photodynamic therapy to manage post-external beam radiation therapy recurrence.     

Antimicrobial photodynamic therapy against pathogenic bacterial suspensions and biofilms using chloro-aluminum phthalocyanine encapsulated in nanoemulsions

Lasers in Medical Science - Antimicrobial photodynamic therapy represents an alternative method of killing resistant pathogens. Efforts have been made to develop delivery systems for hydrophobic...     

Interstitial photodynamic therapy of the canine prostate using intra-arterial administration of photosensitizer and computerized pulsed light delivery

PURPOSE: We determined the feasibility of complete treatment of the canine prostate and long-term effectiveness of interstitial photodynamic therapy using the intra-arterial photosensitizer QLT0074 (benzoporphyrin derivative 1,3-diene C,D-diethylene glycol ester A ring) (QLT, Vancouver, British Columbia, Canada) administration and pulsed light delivery. MATERIALS AND METHODS: The prostate gland of 11 dogs were infused with QLT0074 via the prostatovesical arteries (2 mg drug per artery bilaterally) under fluoroscopic guidance. Immediately following infusion the prostate was surgically exposed and 7 optical fibers with 1.5 cm cylindrical diffusers in after loading sheaths were inserted into the prostate through a template. Light was delivered sequentially to the optic fibers via a computer driven switch system. One dog was sacrificed 6 days after photodynamic therapy to assess acute tissue effects. The other 10 dogs were monitored for clinical tolerance and urinary function, and sacrificed at between 3 and 11 months. Prostate specimens were examined microscopically to evaluate long-term tissue reactions. RESULTS: Comprehensive destruction of the prostate was noted in the acute dog. Except for urinary retention and mild hematuria no other perioperative complications were observed in the chronic dogs. Urodynamic examination did not reveal deleterious bladder and urethral function. Average prostate volume decreased 71% at 3 months and 56% after 6 months (p=0.007 and 0.014, respectively). Microscopic evaluation revealed prostate glandular epithelial atrophy, stromal fibrosis and mononuclear cell infiltration. CONCLUSIONS: Interstitial photodynamic therapy using intra-arterial QLT0074 and pulsed light delivery is safe and feasible for comprehensive destruction of the canine prostate. Clinical trials are required to confirm it for managing prostate diseases.     

Transdermal estradiol therapy for prostate cancer reduces thrombophilic activation and protects against thromboembolism

PURPOSE: Oral estrogens were an effective treatment for prostate cancer but were abandoned because of an increased risk of cardiovascular toxicity and particularly thromboembolism. We have recently shown that transdermal estradiol produces an effective tumor response and negligible cardiovascular toxicity. Here we report the influence of transdermal estradiol therapy on the coagulation profile of men with advanced prostate cancer. MATERIALS AND METHODS: A total of 20 patients with newly diagnosed locally advanced or metastatic prostate cancer were treated using transdermal estradiol patches and the coagulation profile was assessed before and during 12 months therapy. Activation of coagulation was assessed by assaying the levels of activated factor VII (VIIa), activated factor XII (XIIa), prothrombin fragments 1 and 2 (F1 + 2), thrombin-antithrombin III (TAT III) complex and fibrinogen. Inhibition of the coagulation cascade was assayed by protein C, protein S and activated protein C resistance (APC-R). Fibrinolytic activity was determined by assaying tissue plasminogen activator (TPA) and plasminogen activation inhibitor type 1 (PAI-1). D-Dimer levels assessed both coagulation and fibrinolytic (thrombophilic) activity. Venous Duplex, color Doppler ultrasound and photoplethysmography were used to assess for thrombosis. RESULTS: Levels of VIIa and XIIa were unaffected by transdermal estradiol therapy. Although levels of TAT III were increased in some patients at 12 months, the increase was markedly less than that observed historically with equivalent doses of oral estrogens. Levels of the inhibitory and fibrinolytic factors including protein C, protein S, APC-R, TPA and PAI-1 remained stable. Reductions in F1+F2, fibrinogen and D-Dimer levels represented a normalization from increased levels to the physiological range. CONCLUSIONS: These results suggest that transdermal estradiol reduces thrombophilic activation in men with advanced prostate cancer, and protects against the risk of thrombosis.     

Radiation therapy in prostate cancer: whole pelvis with prostate boost or small field to prostate?

The purpose of this retrospective study is to identify prostate cancer patients who would benefit from pelvic nodes irradiation (whole pelvis) as opposed to the small-field irradiation to the prostate only. Between 1975 and 1983, 126 patients were treated by whole pelvis (4,600-5,000 cGY) with prostate boost (2,000 cGY) radiation (WP + P). Median follow-up was six years and six months. Comparison was made with historic control of 116 patients irradiated at the same institutions between 1971 and 1977 by small field to the prostate (P) to a dose of 7,000-7,500 cGY. There was a significant five-year survival improvement in the current WP + P radiation in Stage C (72% vs 40%, p = 0.0004) and Stage B (92% vs 70%, p = 0.025) but not in Stage A2 patients. However, WP + P radiation significantly improved disease-free survival (DFS) in only well and moderately but not in poorly differentiated carcinoma with a combined well and moderately differentiated five-year DFS of 63 percent compared with the 45 percent in P radiation (p = 0.0228). Local tumor control was significantly improved in WP + P radiation in only Stage C cancers with their local recurrence rate 16 percent as compared with the 34 percent in P radiation (p = 0.0172). Although acute radiation reactions were more frequent in WP + P than P radiation (61% vs 41%, p = 0.0022), chronic radiation morbidity in both series were similar. Thus, whole pelvis with prostate boost radiation should be utilized in Stage B and Stage C cancers as this has shown to increase the survival of the patient without increasing chronic radiation morbidity.     

Antimicrobial photodynamic therapy against Propionibacterium acnes biofilms using hypericin (Hypericum perforatum) photosensitizer: in vitro study

Lasers in Medical Science - Acne vulgaris is the most recurring skin condition in the world, causing great harm to the physical and psychological well-being of many patients. Antimicrobial...     

前列腺癌内分泌治疗方法研究及预后分析

目的:探究延长前列腺癌患者进展为激素非依赖性前列腺癌(AIPC)时间的内分泌治疗方法。方法:经直肠活检穿刺证实前列腺癌患者93例,分为3组:22例患者接受双侧睾丸切除加比卡鲁胺联合治疗,行持续性全雄激素阻断(CAD);71例患者行间歇性内分泌治疗方法,其中29例患者行标准间歇性内分泌治疗(IAD),42例患者行改良型间歇性内分泌治疗;两组治疗期用戈舍瑞林或亮丙瑞林联合比卡鲁胺的用药方案,行雄激素最大阻断(MAB),当患者血清PSA下降至<0.2μg/L,维持用药3个月。进入间歇期,IAD组停药,改良型IAD组停用促黄体生成激素释放激素类似物(LHRH-a),但维持使用比卡鲁胺,两组在间歇期内出现PSA持续升高,且大于4μg/L时,则再次启用MAB,直至患者进展为AIPC。比较CAD、IAD及改良型IAD 3组患者疾病随访时间、疾病进展时间及治疗周期。结果:3组患者人口学特征、基线资料及随访时间相似,中位进展时间分别为(26.50±4.15)月、(30.00±7.83)月和(34.93±5.08)月,CAD与标准IAD组比较差异无统计学意义(P=0.143),改良型IAD组与CAD及IAD组比较差异有统计学意义(P=0.001,0.032)。Kaplan-Meier生存分析显示,改良组中位进展时间明显长于标准IAD治疗组(P=0.01)。标准IAD与改良型IAD组平均治疗周期分别为(16.13±3.33)月和(19.58±4.30)月,两组第1治疗周期间歇期分别为(9.6±3.2)月和(14.2±3.7)月,组间比较差异显著(P=0.001)。结论:与CAD和标准IAD比较,改良型IAD可显著延长前列腺癌患者进展为AIPC的时间。     

Focal therapy of prostate cancer: energies and procedures

PurposeOver the last years, focal therapy has emerged as an intermediate management technique between radical approaches (radical prostatectomy, external beam radiation, and brachytherapy) and watchful waiting to manage some early stage prostate cancers (CaP). Different energy modalities are being developed. The aim of this study is to review these energy modalities and their indications.Materials and methodsWe reviewed the literature to concentrate on the practical aspects of focal therapy for CaP with the following key words: photodynamic therapy, high intensity focused ultrasound (HIFU), cryotherapy, focal laser ablation, electroporation, radio frequency, external beam radiation, organ-sparing approach, focal therapy, CaP, and then by cross-referencing from previously identified studies.ResultsProstatic tumor ablation can be achieved with different energies: freezing effect for cryotherapy, thermal effect using focalized ultrasound for HIFU, and using thermal effect of light for focal laser ablation (FLA) and activation of a photosensitizer by light for PDT, among others. Radio frequency and microwave therapy have been tested in this field and demonstrated their usefulness. Electroporation is currently being developed on preclinical models. External beam radiation with microboost on neoplastic foci is under evaluation. HIFU and cryotherapy require the use of sophisticated and expensive machines and, consequently, the procedure is expensive. Laser techniques seem to be less onerous, with the added advantage of size.ConclusionsSeveral energy modalities are being developed to achieve the trifecta of continence, potency, and oncologic efficiency. Those techniques come with low morbidity but clinical experience is limited regarding to oncologic outcome. Comparison of the different focal approaches is complex owing to important heterogeneity of the trials. In the future, it seems likely that each technique will have its own selective indications.     

High-field magnetic resonance imaging of the response of human prostate cancer to Pc 4-based photodynamic therapy in an animal model

INTRODUCTION: High-field magnetic resonance imaging (MRI) is an emerging technique that provides a powerful, non-invasive tool for in vivo studies of cancer therapy in animal models. Photodynamic therapy (PDT) is a relatively new treatment modality for prostate cancer, the second leading cause of cancer mortality in American males. The goal of this study was to evaluate the response of human prostate tumor cells growing as xenografts in athymic nude mice to Pc 4-sensitized PDT. MATERIALS AND METHODS: PC-3, a cell line derived from a human prostate malignant tumor, was injected intradermally on the back flanks of athymic nude mice. Two tumors were initiated on each mouse. One was treated and the other served as the control. A second-generation photosensitizing drug Pc 4 (0.6 mg/kg body weight) was delivered to each animal by tail vein injection 48 hours before laser illumination (672 nm, 100 mW/cm(2), 150 J/cm(2)). A dedicated high-field (9.4 T) small-animal MR scanner was used for image acquisitions. A multi-slice multi-echo (MSME) technique, permitting noninvasive in vivo assessment of potential therapeutic effects, was used to measure the T2 values and tumor volumes. Animals were scanned immediately before and after PDT and 24 hours after PDT. T2 values were computed and analyzed for the tumor regions. RESULTS: For the treated tumors, the T2 values significantly increased (P<0.002) 24 hours after PDT (68.2+/- 8.5 milliseconds), compared to the pre-PDT values (55.8+/-6.6 milliseconds). For the control tumors, there was no significant difference (P = 0.53) between the pre-PDT (52.5+/-6.1 milliseconds) and 24-hour post-PDT (54.3+/-6.4 milliseconds) values. Histologic analysis showed that PDT-treated tumors demonstrated necrosis and inflammation that was not seen in the control. DISCUSSION: Changes in tumor T2 values measured by multi-slice multi-echo MR imaging provide an assay that could be useful for clinical monitoring of photodynamic therapy of prostate tumors.     

DHT in prostate cancer tissue--a guide to management and therapy

In 24 untreated stage D2 prostate cancer patients with prostate DHT levels greater than 2.5 ng/g, 20 initially responded to therapy with partial objective progression (POR) or were objectively stable (OS) for 12 or more months while four patients relapsed in less than 1 year. Of eight patients with prostate DHT levels less than 2.0 ng/g, five had either objective progression or were objectively stable for 6 months or less; two other patients have completed remissions ranging from 16 to 24 months while one patient remains objectively stable for 21 months to date. DHT concentrations were also measured in prostate tissue of patients with advanced prostate cancer in relapse following either DES or castration with or without estrogen therapy. Although castration, medical or surgical, usually leads to DHT concentrations of less than 2.4 ng/g, two out of 20 surgical castrates and four out of nine estrogen-treated patients had values above this level. These differences suggest that (1) increased tissue DHT levels of DES-treated patients may be due to inadequate dosage or decreased compliance, and (2) increased tissue DHT concentrations greater than 2.4 ng/g in castrates suggests an adrenal cortical androgen contribution to the prostate DHT level. These studies suggest that DHT measurements in prostate cancer tissue are of value in predicting response in untreated prostate cancer patients and of directing therapy in patients who are in relapse after orchiectomy or estrogen therapy.     

Androgen and prostate cancer: the role of primary androgen deprivation therapy in localized prostate cancer

BackgroundThe basic mechanisms and clinical efficacy of primary androgen deprivation therapy (PADT), especially combined androgen blockade (CAB) for localized or locally advanced prostate cancer (PCa) have been outlined. An important point relates to which patients are suitable candidates for PADT.MethodsA retrospective review of the efficacy of PADT in 628 patients with localized or locally advanced PCa treated with PADT at seven institutions in Japan was carried out.ResultsIt was found that more than 30% of low- or intermediate-risk localized PCa patients could have their disease controlled over the long-term by PADT alone. Short-term or intermittent PADT could not be recommended because of the possibility of character change in the cancer cells as a result of incomplete androgen ablation.ConclusionAlgorithms are proposed for the treatment of localized PCa not only in low- and intermediate-risk groups, but also in the high-risk group. Future research directions are indicated.