Intravesical administration of EGF- dextran conjugates in patients with superficial bladder cancer.

OBJECTIVES: Overexpression of the epidermal growth factor receptor (EGFR) has been reported in bladder cancer and is a potential target for therapy with radionuclides. In this study, we investigated the binding of EGF-dextran-(99m)Tc to the EGFR. The aim of this study was to determine if intravesically administered EGF-dextran conjungate selectively accumulated in the tumor tissue and to correlate the uptake to tumor characteristics. METHODS: Eight patients received the conjugate intravesically for about 30 min followed by bladder irrigation and then transurethral resection. Radioactivity of the biopsy specimens from normal urothelium and tumor areas was measured in a gamma counter. RESULTS: Five patients received EGF-dextran-(99m)Tc, three received dextran-(99m)Tc and one received only (99m)Tc. The 5 patients who received the complete conjugate had a mean ratio of radioactivity between tumor and normal urothelium of 664:1 (range: 2.4-1,710). The dextran-(99m)Tc showed a slightly increased ratio and (99m)Tc did not bind at all. CONCLUSION: The results are encouraging and further studies are warranted to investigate if EGF-dextran could be effective as intravesical therapy, either conjugated with cystostatic drugs or labeled with suitable radionuclides.

Binding of 125I after administration of 125I-EGF-dextran, 125I-EGF or 125I to human bladder cancer spheroids.

The binding of a targeting agent, 125I-EGF-dextran, to epidermal growth factor (EGF) receptors in tumour spheroids of a human bladder cancer cell line was studied. The accumulation of radioactivity was continuous up to at least 48 h in the peripheral cells of the spheroids, which in comparison with the binding pattern of 125I-EGF indicated that the cells had a limited capacity to degrade the EGF-dextran. The 125I-EGF-dextran was of two different sizes, 28 and 76 kDa, but this did not affect the binding patterns and the results were very similar. The EGF-dextran conjugates had qualities that are of interest for tumour targeting.

Expression of epidermal growth factor receptor in urinary bladder cancer metastases.

Bladder cancers frequently exhibit an increased number of epidermal growth factor receptors (EGFR) in comparison to normal urothelium. The EGFR could potentially be a target for toxic conjugates. The aim of our study was to compare the expression of EGFR in metastases with concurrent or primary tumour in the urinary bladder using immunohistochemical techniques and a monoclonal antibody. Tumour material from 20 patients was investigated. The majority (13/20) of the metastases were homogeneously stained and showed a moderate to strong membranous staining for EGFR. The expression of EGFR in primary bladder tumours and metastases was similar. There was no indication that tumour tissue exposed to chemotherapy or radiation had a decreased number of EGFR. Targeting of the EGFR thus seems potentially applicable to metastatic disease.

The potential of radiolabeled EGF-dextran conjugates in the treatment of urinary bladder carcinoma.

BACKGROUND: Muscle-invasive urothelial carcinoma of the urinary bladder has a poor prognosis in spite of available therapies. These tumors frequently overexpress the epidermal growth factor receptor (EGFr), a possible target for therapeutic conjugates. The aim of this study was to construct an EGF-carbohydrate conjugate that would be potentially useful for both local (i.e., intravesical) and systemic radiotherapy. METHODS: EGF was coupled to periodate activated dextran by reductive amination. Receptor binding tests in vitro were conducted, using the human urothelial carcinoma cell line RT4 and the human malignant glioma cell line U-343-MG as a positive control. In the in vivo experiments, nude mice with subcutaneously grown xenografts of the RT4 tumor were injected intravenously with technetium-99m-labeled EGF conjugates. Samples of organs, blood, and tumors were collected after 24 hours. The radioactive uptake was calculated as a percentage of the dose per gram of tissue. RESULTS: The specific binding in the in vitro experiment was 90-95%. The binding was similar in both cell lines. There was a positive uptake in the tumors in the in vivo experiment, with tumor-to-blood ratios from 2:1 to 6:1. The uptake level in the kidneys was similar to that in the tumors (i.e., approximately 0.05% dose per gram of tissue). The other organs had a lower uptake compared with the tumor uptake. CONCLUSIONS: The results indicate that radiolabeled EGF-dextran has the potential to become a tool for local treatment of recurrent bladder carcinoma. With appropriate modifications, it should be possible to use this conjugate for systemic radiotherapy as well.

Binding, internalization and degradation of EGF-dextran conjugates in two human bladder-cancer cell lines.

Bladder carcinomas often have an increased number of epidermal growth factor (EGF) receptors. The EGF receptors can, in these cases, be targets for toxic conjugates. In this study, EGF-dextran conjugates were used as targeting agents with therapeutic potential. The binding, internalization and degradation of 125I-EGF-dextran conjugates in J82 and RT4, 2 different bladder cancer cell lines, were investigated. The behaviour of 125I-EGF was studied as a comparison. The 125I-EGF-dextran showed a continuous increase in binding up to 24 hr, while 125I-EGF exhibited maximum binding after about 90 min. Both cell lines showed similar binding patterns. The binding of 125I-EGF-dextran and 125I-EGF was, on both cell lines, receptor-specific since the binding could be displaced with non-radioactive EGF. Analysis of internalized and membrane-bound 125I activity after administration of 125I-EGF-dextran showed that most of the activity was membrane-bound. A large part of both the internalized and the membrane-bound activity remained cell-associated up to 24 hr. The internalized and membrane-bound activity after administration of 125I-EGF decreased rapidly and only a small fraction remained cell-associated after 24 hr. 125I-EGF-dextran remained cell-associated, with only a limited release of low- and high-molecular-weight radioactivity throughout the 24-hr period, while 125I-EGF was extensively degraded and released into the incubation medium as low-molecular-weight radioactivity during this time. Several qualities of the 125I-EGF-dextran conjugates might be favourable for targeted radiotherapy.

Chemotherapeutic treatment of recurrent and/or metastatic nasopharyngeal carcinoma: a retrospective analysis of 40 cases.

Authors carried out a review of 40 cases of recurrent and/or metastatic nasopharyngeal carcinoma (NPC) treated with cisplatin-based chemotherapy at the Division of Othorhinolaryngology and the Service of Chemotherapy of the University of Palermo between July 1984 and July 1992. All patients were treated with regimens comprising high dose cisplatin (80-100 mg m-2). Histologically there were 29 squamous cell and 11 undifferentiated NPC. Thirty-nine patients were evaluable for response and toxicity. The overall response rate was 64%, with a 20.5% complete response rate and a 43.5% partial response rate. The mean duration of complete responses was 10.2+months, while that of partial responses was 8.6+months. The mean survival of the whole group was 11.4+months, with four patients alive after 2 years of follow-up. No statistically significant difference in response rate and survival was found between patients with metastatic disease and those with locoregional recurrency, and between patients with squamous cell NPC and those with undifferentiated histology. The employed regimens have been generally well tolerated. These data confirm that NPC is a neoplasm highly responsive to chemotherapy. However, duration of objective response and survival are still largely unsatisfactory.

[Injury patterns in Danish competitive swimming]. / Skademønstret i dansk elitesvømning.

A total of 432 Danish competitive swimmers were asked to complete a questionnaire about the epidemiology of injuries sustained during swimming in the season of 1986/1987. Two hundred and sixty-eight (62%) replied. We found a total of 100 injuries in 80 swimmers with an incidence of 0.9 injuries per swimmer per 1,000 hours of swimming, and a point prevalence of 15% on the day of competition. The shoulder, the back and the knee joint were most commonly involved. No particular swimmingstroke was associated with a greater risk of injury. There was, however, a tendency for butterfly swimmers to have more frequent shoulder injuries and for breaststroke swimmers to have more frequent knee-injuries. Medal winners were significantly more frequently injured. Half of the injured swimmers were seen by a doctor.