Biomedical subjects

P-U Malmström

Publications and source records attributed to P-U Malmström.

5 recordsLinked to original sources

PubMed2006

Astatinated trastuzumab, a putative agent for radionuclide immunotherapy of ErbB2-expressing tumours.

The anti-ErbB2 antibody trastuzumab is used for the treatment of patients with advanced breast cancer, resulting in a response rate of 40-60%. Coupling with a cytotoxic nuclide, e.g. alpha-emitting 211At, may further increase tumour response. The tumour-targeting properties of trastuzumab, astatinated using N-succinimidyl-para-(tri-n-methylstannyl)-benzoate, were evaluated and compared with those of radioiodinated trastuzumab in this study. We found that astatinated trastuzumab retains high specificity towards ErbB2. While the immunoreactive fraction of radioiodinated trastuzumab was higher than that of astatinated trastuzumab (76+/-9% versus 54+/-28%), both radioconjugates showed high affinity (KD 0.75+/-0.16 nM versus 1.8+/-0.3 nM). A growth inhibition study indicated a dose-dependent cell deactivation, in which approximately 74 cell-associated astatine decays per cell gave a survival fraction of 4.5+/-0.8x10(-4). Results of a comparative animal study on normal mice gave no indication that astatination would have any adverse effects on the biodistribution of the antibody. In conclusion, the results of the study suggest that astatinated trastuzumab is a promising candidate for treating ErbB2-expressing tumours.

Animals↗

PubMed2005

Optimization of the MB49 mouse bladder cancer model for adenoviral gene therapy.

Bladder cancer is regarded as a promising candidate for innovative therapies in the field of immune and gene therapy. In this paper, we present the subcutaneous, metastatic and a novel orthotopic model of murine MB49 bladder cancer in C57BL/6 mice. We further show the potential of using adenoviral vectors together with different transduction enhancers to augment in vivo gene delivery. Finally, we present candidate genes for tumour detection, therapy or targeting. The MB49 tumour grew rapidly in mice. The subcutaneous model allowed for tumour detection within a week and the possibility to monitor growth rate on a day-by-day basis. Injection of MB49 cells intravenously into the tail vein gave rise to lung metastases within 16 days, while instillation of tumour cells into pretreated bladders led to a survival time of 20-40 days. Adenoviral vectors can be used as a vehicle for gene transfer to the bladder. By far, the most potent transduction enhancer was Clorpactin, also known as oxychlorosene. Last, we show that MB49 cells express tumour-associated antigens like bladder cancer-4, prostate stem cell antigen and six-transmembrane epithelial antigen of the prostate. Given the possibility for efficient genetic modification of the bladder and the presence of known tumour antigens, the MB49 models can be used in innovative ways to explore immunogene therapy.

Adenoviridae↗

PubMed2003

[Bladder cancer and the sentinel node concept].

PURPOSE: Lymph node status is one of the most important prognostic factors in muscle-invasive bladder cancer. The extent of lymphadenectomy performed in conjunction with cystectomy and the question as to whether this is a staging or therapeutic intervention are matters of discussion. The aim of this study was to evaluate the sentinel node (SN) concept and to correlate findings with tumour status in excised regional lymph nodes. MATERIAL AND METHOD: 26 patients scheduled for cystectomy were investigated with preoperative lymphoscintigraphy, peroperative dye detection (Patent Blue) and dynamic lymphoscintigraphy (Nanocoll or Albures 50 MBq/ml). The substances were injected adjacent to the tumour in the detrusor muscle. RESULTS: Sentinel nodes were detected in 21 of the 26 of the investigated patients. 7/21 SN were located outside the obturator fossa. Of the eight patients with lymph node metastasis, five displayed metastasis in lymph nodes outside the obturator fossa. There was one false negative SN in a patient with multifocal tumour, while in the other seven patients with lymph node metastasis, these were detected in the SN. CONCLUSION: Sentinel node detection is possible in most cases of bladder cancer scheduled for cystectomy. The significance of utilizing this method to detect lymph node metastasis outside the obturator fossa warrants further investigation.

Cystectomy↗

PubMed2003

[Transitional cell carcinoma of the prostate in cystoprostatectomy specimens].

PURPOSE: Transitional cell carcinoma (TCC) of the prostate/prostatic urethra is a risk factor for urethral recurrence after radical cystoprostatectomy for TCC. Using conventional sectioning techniques, prostate involvement (prostatic urethra, acini, ducts and/or stroma) has been detected in a range of 10-20% of the patients, whereas transversal whole mount sectioning has revealed 43 % prostate involvement in two reported series. Due to different mechanisms of prostate involvement (intraurethral, extravesical and direct overgrowth into the prostatic stroma), preoperative transurethral biopsies of the prostate might not accurately determine such involvement. In this study we examine the prostate using a longitudinal whole mount sectioning technique, correlate TCC of the prostate with the characteristics of the bladder tumour and, thus, validate the preoperative transurethral resection biopsies. MATERIAL AND METHODS: Patients scheduled for cystoprostatectomy or cystoprostatourethrectomy were investigated by preoperative resection biopsies from the prostatic urethra and mapping of the bladder. The cystectomy specimen was fixated with the bladder filled with formalin, and the prostate and bladder neck examined using longitudinal whole mount sectioning. RESULTS: In 13 of the 43 (30%), patients TCC was identified in the prostate. Of these 13 patients, 9 had been identified in the preoperative resection biopsies from the prostatic urethra. Of the patients with prostatic involvement, 46% had carcinoma in situ (Cis) in the bladder neck/trigone and 38% had multifocal Cis in the bladder. Comparing this to the group of patients without prostatic involvement, the respectively figures are 20% and 23%. A tumour in the trigone, either invasive or Cis, was detected in 5/13 patients with prostatic involvement as compared to one patient (3%) without TCC of the prostate. Multiple bladder tumours were more common in patients with prostatic involvement and were larger (3.2 cm compared to 2.2 cm). CONCLUSIONS: Preoperative resection biopsies from the prostatic urethra do not always detect TCC in the prostate. Cis in the bladder neck/trigone or multifocal and multiple bladder tumours could be risk factors for prostate involvement of TCC.

Biopsy↗

PubMed2002

Human urinary bladder carcinomas express adenovirus attachment and internalization receptors.

The use of adenoviral vectors as potent gene delivery systems requires expression of the Coxsackievirus/adenovirus receptor (CVADR) on the target cell surface. This receptor is important for virus attachment to the cell surface. For effective internalization of the vector into the target cell the integrins alpha(v)beta(3) and/or alpha(v)beta(5) are needed. Since there have been reports of loss of CVADR in bladder cancer cell lines, we wanted to investigate the expression of this receptor in bladder carcinoma biopsies. Surgical biopsies, as well as five human bladder cancer cell lines, were analyzed for expression of CVADR, the integrins alpha(v)beta(3) and alpha(v)beta(5) and MHC class I. Further, we studied the ability to transduce these cell lines using adenoviral vectors. Immunohistochemistry revealed that all biopsies (27/27) were positive for CVADR. Some variation in expression was evident, and superficially growing tumors stained more strongly than invasive ones. Most human tumors expressed the integrin alpha(v)beta(5) (14/24), whereas integrin alpha(v)beta(3) was less frequently seen (3/20). The established cell lines were efficiently transduced with adenoviral vectors, and transduction could be reduced with anti-CVADR antibodies. The abundance of appropriate viral receptors on tumor biopsy cells is a further argument for using adenoviral vectors in gene therapy of bladder cancer.

Adenoviridae↗