SVIBOR - Project code: 3-01-223

MINISTRY OF SCIENCE AND TECHNOLOGY

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Project code: 3-01-223


INVESTIGATION ON HORMONAL DEPENDENCY OF PROSTATE TUMORS


Main researcher: TARLE, MARKO (71894)


Assistants
Type of research: applied
Duration from: 01/01/91. to 12/31/94.
Papers on project (total): 35
Papers on project quoted in Current Contents: 25
Institution name: Bolnica "Sestre milosrdnice", Zagreb (134)
Department/Institute: Division of prostate tumors diagnosis and monitoring, Clinic of Nuclear Medicine and Oncology, Univ.Hosp.Sestre Milosrdnice,
Address: Vinogradska c. 29
City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (41)174666-228
Fax: 385 (41) 172 453
Phone: 385 (0)
Phone: 385 (0)
Phone: 385 (41) 174666-228
Fax: 385 (41) 172 453
Summary: The relationship between serum osteocalcin and cortisol level was studied in hormonally treated and progressive prostate cancer patients. Neuroendocrine structures in adenocarcinoma that increase serum NSE (and CEA) level are found to refractory to androgen deprivation. NK values measured under in vivo conditions are recognized as a sensitive probe for circulating tumor cells. Blood TPS value is found to be the valuable tool in monitoring metastatic patients. Correlation between serum PSA level and a decreased tumor differentiation in hormonally treated and progressive subjects gave a bell-shaped curve with the maximum associated with moderately differentiated tumors. In ongoing studies we investigate the recognition of small cell cancer structures within adenocarcinoma by assessing circulating TPS, PSA, PAP, NSE levels and tissue chromogranin A marker, the relationship between the increase in serum TPS level and a loss in tumor differentiation, the development of 'pure'small cell prostate tumor and sarcomatoid tumor from high grade adenocarcinoma by a serial measurement of specific immunohistochemical markers and tumor serotests, the pronounced and transient peak in serum TPS level that was found in over 50% of responders to androgen deprivation with well and moderately differentiated tumors, immunohistochemical studies of benign hypertrophy, prostatic intraepithelial neoplasia, low and high grade carcinom of the prostate by using a wide spectrum of tissue and serum markers, mechanism of action of flutamide monotherapy in relations to apoptosis. In the years 1994/95 treatment of poorly differentiated cancer by applying maximal androgen blockade was studied. The role of TPS serotest was redefined as a marker of circulating tumor cell or their degradation products. The investigation of free(F), bound (B) and total (T) blood PSA fraction gave an excellent parameter (F/T)x100 PSA used for the distinction of really benign atypical prostate from the same entity that will progress soon into aggressive metastatic cancer. This same parameter was found to be exceedingly useful prognostic index during monitoring treated patients with prostatic carcinoma. This parameter is already clinically used. Serotest PSA, PAP, TPS, TPA, (F/T)x100 PSA and NK cell activity data are studied in subjects treated with cytotoxic drugs such as 5-FU, endoxan or their combination.

Keywords: Prostate cancer, immunohistochemical and serotest markers, NK activity, proliferation, apoptosis, PSA, PAP, CEA, NSE, TPS, cytokeratins, chromogranin A, osteocalcin, early diagnosis, monitoring protocols, total andogen blockade,cytotoxic treatment,(F/T)x100 PSA, diagnosis, treatment.

Research goals: During the past decade this project was aimed at theinvestigation of natural history of prostate cancer. 1. Onlya small fraction of prostatic tumor are initially manifest. Themajority remains silent during lifetime.The early distinctionbetween the latent and manifest form of cancer appears to be ofthe utmost clinical importance. 2. Androgen deprivation is apalliative treatment due to apoptosis of secretory cells whilebasal cells, being androgen independent, remain intact. Thesecells are the potential source of hormone refractory cancer. Weinvestigate the appearance of hormonally independent carcinomaafter relapse of hormone dependent disease by assessing tissuecytokeratin expression together with other relevant markers.3.Endocrine cells regulate tumor proliferation by the paracrineaction. We investigate the development of aggressiveneuroendorine tumors. 4. Protocols that use PSA and PAP serotestsfor monitoring poorly differentiated carcinomas are of limitedclinical use due to hormonal dependency of these markers. Westudy the clinical application of cell proliferation markers inhormonally treated patients. 5. Apoptosis is investigated inprostatic adenocarcinoma by using immunohistochemical andserotest markers. The obtained data are already used in clinical practice. In the period 1994/95 studies were aimed at 1.monitoring of cytotoxic treatment (5-FU, endoxan) by appying PSA. PAP, TPS, NK cell activity data,and a new (F/T)x100 PSA parameter;2. the application of free (F), bound (B), and total (T) PSA fraction in the circulation that expressed as (F/T)x100 PSA value is useful in differentiating benign atypical prostate from the same that is already transformed into aggressive and metastatic cancer; 3. this same parameter is studied with success as a prognostic index in monitoring treated patients with prostatic carcinoma; 4.data that inform us on the usefulness of the maximal androgen blockade in patients with a high Gleason score cancer (>6).
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