Photodynamic therapy in the canine prostate using motexafin lutetium.

Our purpose was to determine the feasibility of comprehensive treatment of the canine prostate with photodynamic therapy (PDT) using motexafin lutetium (Lu-Tex) and to evaluate the toxicity and tissue effects associated with this treatment. Twenty-five adult male beagles with normal prostate glands were given an i.v. injection of the second-generation photosensitizer Lu-Tex (2-6 mg/kg). An additional two dogs were used as controls and did not receive any photosensitizing drug. All 27 dogs underwent laparotomy to expose the prostate. Three hours postinjection, a total dose of 75-150 J/cm of 732 nm laser light was delivered interstitially and/or transurethrally to the prostate via cylindrical diffusing fibers. Dogs were euthanized between 2 days and 3 months after PDT. All subjects were monitored for clinical evidence of toxicity. Specimens were examined macroscopically and microscopically to characterize the tissue reaction and assess extent of tissue effect as a result of treatment. Interstitial and/or transurethral PDT were successfully delivered in all dogs with no perioperative complications. No clinical evidence of acute urinary obstruction or rectal bleeding was noted. At all dose levels, macroscopic and microscopic evaluation revealed a prostatic tissue reaction characterized initially (within 48 h) by inflammation and necrosis followed by fibrosis and glandular epithelial atrophy. Comprehensive treatment of the entire prostate could be achieved using the interstitial alone approach or combined transurethral and interstitial approach. The transurethral alone approach did not result in complete coverage of the prostate. Dogs receiving transurethral or combined interstitial and transurethral treatment developed erythema and urethral epithelial disruption at all dose levels. Those receiving combined treatment at the highest dose level (Lu-Tex 6 mg/kg, 150 J/cm light) developed urethral fistulae and peritonitis. Dogs treated with the interstitial alone approach were found to have the least amount of urethral damage. Comprehensive treatment of the canine prostate with Lu-Tex PDT is feasible using an interstitial alone or combined interstitial and transurethral approach. The interstitial alone technique results in the least amount of toxicity. The prostatic tissue reaction to treatment is characterized by initial inflammation and necrosis followed by fibrosis and glandular epithelial atrophy.

Hypoxia in human intraperitoneal and extremity sarcomas.

PURPOSE: The presence of hypoxia, measured by needle electrodes, has been shown to be associated with poor patient outcome in several human tumor types, including soft tissue sarcomas. The present report emphasizes the evaluation of hypoxia in soft tissue sarcomas based upon the binding of the 2-nitroimidazole drug EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide). EF5 has previously been shown to be predictive of radiation response in animal tumors and in in vitro studies. We have also previously reported studies of EF5 binding in human squamous cell tumors. Using fluorescent immunohistochemical techniques, we provide data on the presence and distribution of EF5 binding, as a surrogate for hypoxia, in human spindle cell tumors. METHODS AND MATERIALS: Patients with spindle cell tumors who were scheduled for tumor surgery were asked to participate in the Phase I trial of EF5. Approximately 48 h preoperatively, EF5 was administered i.v. at doses between 9 and 21 mg/kg. Binding in frozen sections of biopsied tissues was determined using monoclonal antibodies labeled with the green-excited, orange-emitting fluorescent dye, Cy3. Calibration studies were performed in vitro by incubating fresh tumor tissue cubes obtained from each patient with EF3 (an analog of EF5) under hypoxic conditions ("reference binding"). The goal of these calibration studies was to quantify the maximal binding levels possible in individual patient's tissues. The relationship between binding (in situ based on EF5 binding) and reference binding (in vitro based on EF3 binding) was determined. RESULTS: Eight patients were studied; 3 of these patients had gastrointestinal stromal tumors (GIST). The incubation of tumor tissue cubes in EF3 under hypoxic conditions demonstrated that all tumors bound drug to a similar extent. Reference binding showed a 3.2-fold variation in median fluorescence (113-356) on an absolute fluorescence scale, calibrated by a Cy3 dye standard. In situ binding in the brightest tumor section varied by a factor of 25.4 between the lowest and highest binding tumor (7.5-190.2). Heterogeneity of highest binding was greater between tumors than within individual tumors. A correspondence between EF5 binding and Eppendorf needle electrode studies was seen in the 5 patients with non-GISTs. CONCLUSION: Inter- and intratumoral heterogeneity of EF5 binding in spindle cell tumors has been documented. Patterns of binding consistent with diffusion limited hypoxia are present in human spindle cell neoplasms.

Photodynamic therapy in the treatment of cancer: current state of the art.

Photodynamic therapy (PDT) is a treatment modality using a photosensitising drug and light to kill cells. The clinical use of PDT requires the presence of a photosensitising agent, oxygen and light of a specific wavelength which matches the absorption characteristics of the photosensitiser. When the photosensitiser is activated by the appropriate wavelength of light, it interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. The appeal of PDT in oncology is that the photosensitiser tends to be retained in tumour tissues for a longer period of time as compared with normal tissues resulting in a large therapeutic index. This potential for minimal normal tissue toxicity has prompted an interest in studying PDT as a cancer treatment. Furthermore, the use of PDT is not precluded by prior radiotherapy, chemotherapy or surgery. The development of PDT has been hampered by the limitations of the older photosensitisers, namely limited depth of tissue penetration, and extended skin phototoxicity which limits the number of applications during a course of treatment. However, newer photosensitisers are being developed which allow greater depth of tissue penetration and have minimal skin phototoxicity allowing for multiple fractionated treatments. With such advancements, PDT has great potential to become an integral part of cancer treatment in the future.

Radiation therapy for chest wall recurrence of breast cancer after mastectomy in a favorable subgroup of patients.

PURPOSE: Long-term outcome after radiation therapy for local-regional recurrence of breast cancer after mastectomy is generally poor. This study was performed to evaluate the long-term outcome for a potentially favorable subgroup of patients with chest wall recurrence. METHODS AND MATERIALS: Of 71 patients with an isolated local-regional recurrence of breast cancer after mastectomy, 18 were identified who met the following favorable selection criteria: 1) a disease-free interval after mastectomy of 2 years or more, 2) an isolated chest wall recurrence, and 3) tumor size < 3 cm or complete excision of the recurrent disease. All 18 patients were treated with local-regional irradiation between 1967 and 1988. Radiotherapy (RT) was delivered to the chest wall to a median total dose of 60 Gy (range 30-66 Gy). Four patients received adjuvant chemotherapy and six patients received adjuvant hormonal therapy. RESULTS: With a median follow-up of 8.4 years, nine of 18 patients were alive and free of disease. The 10-year actuarial overall and cause-specific survivals were 72% and 77%, respectively. The 10-year actuarial relapse-free survival and local control were 42% and 86%, respectively. CONCLUSION: Treatment for a local-regional recurrence of breast cancer after mastectomy in a favorable subgroup of patients results in a high rate of long-term survival as well as excellent local control. Aggressive treatment is warranted in this favorable subgroup of patients.

cAMP and protein kinase A stimulate acidification of rat liver endosomes in the absence of chloride.

Endosomes and lysosomes are acidified by an electrogenic proton pump in parallel with a chloride conductance and in kidney both of these may be regulated by cAMP. In vitro exposure of isolated rat liver endosomes to cAMP, PKA and GTP-gamma S stimulated acidification of "early" endosomes with or without C1-, but not in the absence of K+. cAMP and PKA also increased acidification rates of purified "late" endosomes, multivesicular bodies, CURL vesicles and lysosomes. "Early" endosomes prepared from livers perfused with cAMP also exhibited increased rates of acidification. cAMP and PKA had no consistent effects on steady-state intravesicular pH or proton efflux rates. Thus, acidification of several types of liver endocytic vesicles was stimulated by cAMP and PKA in the presence and absence of chloride, possibly due to changes in the proton pump itself and/or a cation conductance.