Canine lung cancer

Preclinical Studies in Normal Canine Prostate of a Novel Palladium-Bacteriopheophorbide (WST09) Photosensitizer for Photodynamic Therapy of Prostate Cancer (para)

ABSTRACT

Photodynamic therapy (PDT) uses light to activate a photosensitizer to achieve localized tumor control. In this study, PDT mediated by a second-generation photosensitizer, palladium-bacteriopheophorbide WST09 (Tookad) was investigated as an alternative therapy for prostate cancer. Normal canine prostate was used as the animal model. PDT was performed by irradiating the surgically exposed prostate superficially or interstitially at 763 nm to different total fluences (100 or 200 J/cm^sup 2^; 50, 100 or 200 J/cm) at 5 or 15 min after intravenous administration of the drug (2 mg/kg). Areas on the bladder and colon were also irradiated. The local light fluence rate and temperature were monitored by interstitial probes in the prostate. All animals recovered well, without urethral complications. During the 1 week to 3 month posttreatment period, the prostates were harvested for histopathological examination. The PDT-induced lesions showed uniform hemorrhagic necrosis and atrophy, were well delineated from the adjacent normal tissue and increased linearly in diameter with the logarithm of the delivered light fluence. A maximum PDT-induced lesion size of over 3 cm diameter could be achieved with a single interstitial treatment. There was no damage to the bladder or rectum caused by scattered light from the prostate. The bladder and rectum were also directly irradiated with PDT. At 80 J/cm^sup 2^, a full-depth necrosis was observed but resulted in no perforation. At 40 J/cm2, PDT produced minimal damage to the bladder or rectum. On the basis of optical dosimetry, we have estimated that 20 J/cm^sub 2^ is the fluence required to produce prostatic necrosis. Thus, the normal structure adjacent to the prostate can be safely preserved with careful dosimetry. At therapeutic

PDT levels, there was no structural or functional urethral damage even when the urethra was within the treated region. Hence, Tookad-PDT appears to be a promising candidate for prostate ablation in patients with recurrent, or possibly even primary, prostate cancer.

Abbreviations: Deff, effective attenuation depth; H&E, hematoxylin and eosin; HIFU, high-intensity focused ultrasound; i.v., intravenous; PDT, photodynamic therapy; SQ, subcutaneous; Tookad, palladium-bacteriopheophorbide, WST09.

INTRODUCTION

In the United States, prostate cancer is the most common cancer in men, and the second leading cause of cancer death among them (1). Although there are only palliative treatments for metastatic prostate cancer, early-stage prostate cancer is often confined within the organ and is treated with curative intent by surgery, radiation therapy (brachytherapy, external beam or a combination of both), or by both surgery and radiation, which offer a cure rate ranging from 50% to 70% (2-4). Significant side effects are reported to be associated with these current therapies. Approximately half of the patients suffer from impotency after either radiation or surgery (4,5). Other severe complications include urinary incontinence and injuries to nearby structures after radical prostatectomy (surgical removal of prostate), and bladder and bowel dysfunction after radiation therapy. Hyperthermia has been used in both benign hyperplasia and cancer of the prostate, primarily to relieve the urinary symptoms. The outcomes of the treatments appear to be modest (6). The primary limitation of hyperthermia is the difficulty in achieving a temperature (in the prostatic tissue) high enough to cause direct cell killing, using current technologies for energy delivery devices. Other drawbacks are that several sessions are required to provide even temporary relief of the symptoms, and there is the potential to develop prostatorectal fistula (6). Image-guided cryotherapy provides another option for the treatment of primary prostate cancer. But available data indicate that the results of cryotherapy are comparable with those of both radiotherapy and radical prostatectomy (7). High-intensity focused ultrasound (HIFU) is a minimally invasive technique and can induce thermal lesions at depths >10 cm. Preliminary results showed that transrectal HIFU could induce partial ablation with high rates of negative biopsies, low prostate-specific antigen and a low complication rate, although some patients might need transurethral debris resection (8). There is still a need for an alternative or adjunctive therapy to treat localized prostate cancer, either as a primary modality or as a postradiation failure.

Photodynamic therapy (PDT) is an evolving cancer treatment modality. The procedure involves administration of a light-sensitive drug (photosensitizer). A time is allowed for the drug to be taken up in the target tissue that is then irradiated with light of appropriate wavelength to activate the photosensitizer. This initiates a sequence of photochemical, chemical and biological reactions, which ultimately lead to cell death (9). PDT using the first-generation photosensitizer Photofrin (Axcan, Montreal, Canada) has been approved by the U.S. Food and Drug administration for treatment of selected types of tumors such as esophageal and lung cancers. The feasibility of using PDT on animal models to treat prostate cancer has been investigated in this laboratory as well as in several others. There are several reports of PDT in a rat prostate tumor model, which indicate that PDT can effectively kill prostate tumors (10-14). Canine prostate has been used as an animal model for studying PDT in prostate because of its resemblance both in physical size and in anatomical structure to that of humans. In vivo optical properties of canine prostate have been studied for Photofrin-mediated PDT in this laboratory and were found to be similar to those of in vivo human prostate (15-17). Canine prostate tissue responses to PDT mediated by various photosensitizing agents were investigated (18-22), and the general consensus is that, given a fixed optical dose, the volume of tissue damage is rather unpredictable.

The present work is a pilot study using a second-generation photosensitizer, palladium-bacteriopheophorbide, WST09 (Tookad; Steba Biotech, Toussus-Le-Noble, France), to ablate prostatic tissue. Tookad is a novel and pure palladium-substituted bacteriochlorophyll derivative (Fig. 1). It has a maximum absorption wavelength in the near-infrared (763 nm) with a high extinction coefficient (epsilon = 10^sup 5^ mol^sub -1^ cm-^sup -1^ in chloroform [23]). The drug has extremely fast pharmacokinetics-cleared rapidly from the circulation (95% in 15 min in mice) and from other tissue in the order of a few hours (A. Scherz, personal communication). Its effectiveness on human prostatic small-cell carcinoma has been demonstrated on a mouse xenografts model (Y. Salomon, personal communication).

The objectives of this study were to (1) demonstrate that Tookad-PDT can destroy a clinically significant volume of prostate tissue; (2) determine the optimum drug-light time interval; (3) assess the dependence of the size of the PDT lesion on the light dose; and (4) determine the potential phototoxic damage to adjacent tissues and normal prostatic structures, including the bladder, rectum and urethra, and thereby evaluate the potential effectiveness and morbidity of the treatment. Because the ultimate clinical objective requires that the whole prostate be treated because of the poor differentiation from normal tissue and the multinodular nature of prostate cancer, it was critical for this study to use a large-animal model in which the size of the prostate is similar to that in humans. Hence, canines were selected. The limitation is that there is no readily available prostate cancer model in the canine (other than serendipitous spontaneous disease). Hence, the study reports only on the response of normal prostate tissue. But there are reports indicating that, if all other treatment parameters are identical, PDT is likely to be equally effective in destroying normal tissue and the embedded cancerous tissue from the same tissue origin (24-29). Again, given that the selective destruction of tumor is not an absolute prerequisite for PDT to be applied successfully in patients, the results obtained are directly useful for the design of clinical trials.

DISCUSSION