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Filename: drivers/Session_files_driver.php
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File: /var/www/html/index.php
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Function: require_once
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Filename: Session/Session.php
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File: /var/www/html/index.php
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Function: require_once
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Message: Undefined array key "choices"
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 249
Function: _error_handler
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Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
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Function: _error_handler
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Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
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Function: _error_handler
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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Function: _error_handler
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Filename: models/Detail_model.php
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Function: strpos
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Function: insertAPISummary
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Function: require_once
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Filename: helpers/my_audit_helper.php
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Function: str_replace
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Function: formatAIDetailSummary
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Function: require_once
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Filename: controllers/Detail.php
Line Number: 256
Backtrace:
File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 256
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File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
Line Number: 256
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File: /var/www/html/application/controllers/Detail.php
Line: 256
Function: _error_handler
File: /var/www/html/index.php
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Message: Undefined array key "usage"
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
Line: 257
Function: _error_handler
File: /var/www/html/index.php
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Message: Trying to access array offset on value of type null
Filename: controllers/Detail.php
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File: /var/www/html/application/controllers/Detail.php
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Function: _error_handler
File: /var/www/html/index.php
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Filename: controllers/Detail.php
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Function: _error_handler
File: /var/www/html/index.php
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Filename: controllers/Detail.php
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Filename: controllers/Detail.php
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Filename: controllers/Detail.php
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Filename: controllers/Detail.php
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Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
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Function: require_once
Androgen ablating drugs increase life expectancy in men with metastatic prostate cancer, but resistance inevitably develops. In a majority of these recurrent tumors, the androgen axis is reactivated in the form of increased androgen receptor (AR) expression. Targeting proteins that are expressed as a down-stream effect of AR activity is a promising rationale for management of this disease. The humanized IgG1 antibody hu11B6 internalizes into prostate and prostate cancer (PCa) cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate specific enzyme governed by the AR-pathway. In a previous study, hu11B6 conjugated with Actinium-225 (Ac), a high linear energy transfer (LET) radionuclide, was shown to generate an AR-upregulation driven feed-forward mechanism that is believed to enhance therapeutic efficacy. We assessed the efficacy of hu11B6 labeled with a low LET beta-emitter, Lutetium-177 (Lu) and investigated whether similar tumor killing and AR-enhancement is produced. Moreover, single-photon emission computed tomography (SPECT) imaging of Lu is quantitatively accurate and can be used to perform treatment planning. [Lu]hu11B6 therefore has significant potential as a theranostic agent. : Subcutaneous PCa xenografts (LNCaP s.c.) were grown in male mice. Biokinetics at 4-336 h post injection and uptake as a function of the amount of hu11B6 injected at 72 h were studied. Over a 30 to 120-day treatment period the therapeutic efficacy of different activities of [Lu]hu11B6 were assessed by volumetric tumor measurements, blood cell counts, molecular analysis of the tumor as well as SPECT/CT imaging. Organ specific mean absorbed doses were calculated, using a MIRD-scheme, based on biokinetic data and rodent specific S-factors from a modified MOBY phantom. Tumor tissues of treated xenografts were immunohistochemically (IHC) stained for Ki-67 (proliferation) and AR, SA-β-gal activity (senescence) and analyzed by digital autoradiography (DAR). : Organ-to-blood and tumor-to-blood ratios were independent of hu11B6 specific activity except for the highest amount of antibody (150 µg). Tumor accumulation of [Lu]hu11B6 peaked at 168 h with a specific uptake of 29 ± 9.1 percent injected activity per gram (%IA/g) and low accumulation in normal organs except in the submandibular gland (15 ± 4.5 %IA/g), attributed to a cross-reaction with mice kallikreins in this organ, was seen. However, SPECT imaging with therapeutic amounts of [Lu]hu11B6 revealed no peak in tumor accumulation at 7 d, probably due to cellular retention of Lu and decreasing tumor volumes. For [Lu]hu11B6 treated mice, tumor decrements of up to 4/5 of the initial tumor volume and reversible myelotoxicity with a nadir at 12 d were observed after a single injection. Tumor volume reduction correlated with injected activity and the absorbed dose. IHC revealed retained expression of AR throughout treatment and that Ki-67 staining reached a nadir at 9-14 d which coincided with high SA- β-gal activity (14 d). Quantification of nuclei staining showed that Ki-67 expression correlated negatively with activity uptake. AR expression levels in cells surviving therapy compared to previous timepoints and to controls at 30 d were significantly increased (p = 0.017). : This study shows that hu11B6 labeled with the low LET beta-emitting radionuclide Lu can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematological side-effects. The tumor response correlated with the absorbed dose both on a macro and a small scale dosimetric level. Analysis of AR staining showed that AR protein levels increased late in the study suggesting a therapeutic mechanism, a feed forward mechanism coupled to AR driven response to DNA damage or clonal lineage selection, similar to that reported in high LET alpha-particle therapy using Ac labeled hu11B6, however emerging at a later timepoint.
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Source |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6531309 | PMC |
http://dx.doi.org/10.7150/thno.31179 | DOI Listing |
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