TY  - JOUR
A1  - Hecht, Markus
A1  - Erber, Sonja
A1  - Harrer, Thomas
A1  - Klinker, Hartwig
A1  - Roth, Thomas
A1  - Parsch, Hans
A1  - Fiebig, Nora
A1  - Fietkau, Rainer
A1  - Distel, Luitpold V.
T1  - Efavirenz Has the Highest Anti-Proliferative Effect of Non-Nucleoside Reverse Transcriptase Inhibitors against Pancreatic Cancer Cells
T2  - PLoS ONE
N2  - Background 
Cancer prevention and therapy in HIV-1-infected patients will play an important role in future. The non-nucleoside reverse transcriptase inhibitors (NNRTI) Efavirenz and Nevirapine are cytotoxic against cancer cells in vitro. As other NNRTIs have not been studied so far, all clinically used NNRTIs were tested and the in vitro toxic concentrations were compared to drug levels in patients to predict possible anti-cancer effects in vivo. 

Methods 
Cytotoxicity was studied by Annexin-V-APC/7AAD staining and flow cytometry in the pancreatic cancer cell lines BxPC-3 and Panc-1 and confirmed by colony formation assays. The 50% effective cytotoxic concentrations (EC50) were calculated and compared to the blood levels in our patients and published data. 

Results 
The in vitro EC50 of the different drugs in the BxPC-3 pancreatic cancer cells were: Efavirenz 31.5\(\mu\)mol/l (= 9944ng/ml), Nevirapine 239\(\mu\)mol/l (= 63786ng/ml), Etravirine 89.0\(\mu\)mol/l (= 38740ng/ml), Lersivirine 543\(\mu\)mol/l (= 168523ng/ml), Delavirdine 171\(\mu\)mol/l (= 78072ng/ml), Rilpivirine 24.4\(\mu\)mol/l (= 8941ng/ml). As Efavirenz and Rilpivirine had the highest cytotoxic potential and Nevirapine is frequently used in HIV-1 positive patients, the results of these three drugs were further studied in Panc-1 pancreatic cancer cells and confirmed with colony formation assays. 205 patient blood levels of Efavirenz, 127 of Rilpivirine and 31 of Nevirapine were analyzed. The mean blood level of Efavirenz was 3587ng/ml (range 162-15363ng/ml), of Rilpivirine 144ng/ml (range 0-572ng/ml) and of Nevirapine 4955ng/ml (range 1856-8697ng/ml). Blood levels from our patients and from published data had comparable Efavirenz levels to the in vitro toxic EC50 in about 1 to 5% of all patients. 

Conclusion 
All studied NNRTIs were toxic against cancer cells. A low percentage of patients taking Efavirenz reached in vitro cytotoxic blood levels. It can be speculated that in HIV-1 positive patients having high Efavirenz blood levels pancreatic cancer incidence might be reduced. Efavirenz might be a new option in the treatment of cancer.
KW  - human hepatic cells
KW  - active antiretroviral therapy
KW  - differentiated thyroid tumor
KW  - HIV-infected patients
KW  - pharmacokinetic interaction
KW  - LINE-1 retrotransposition
KW  - HIV-1-infected subjects
KW  - healthy volunteers
KW  - prostate cancer
KW  - i-131 uptake
Y1  - 2015
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/15169
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-151694
VL  - 10
IS  - 6
ER  -