Abstract
Cervical cancer caused by the infection with the human papillomavirus (HPV) remains the fourth leading killer of women worldwide. Therefore, more efficacious treatments are needed. We are developing radioimmunotherapy (RIT) of HPV-positive cervical cancers by targeting E6 and E7 viral oncoproteins expressed by the cancer cells with the radiolabeled monoclonal antibodies (mAbs). To investigate the influence of different radionuclides on the RIT efficacy-we performed RIT of experimental cervical cancer with Rhenium-188 ((188) Re) and Lutetium-177 ((177) Lu)-labeled mAb C1P5 to E6. The biodistribution of (188) Re- and (177) Lu-labeled C1P5 was performed in nude female mice bearing CasKi cervical cancer xenografts and the radiation dosimetry calculations for the tumors and organs were carried out. For RIT the mice were treated with 7.4 MBq of either (188) Re-C1P5 or (177) Lu-C1P5 or left untreated, and observed for their tumor size for 28 days. The levels of (188) Re- and (177) Lu-C1P5 mAbs-induced double-strand breaks in CasKi tumors were compared on days 5 and 10 post treatment by staining with anti-gamma H2AX antibody. The radiation doses to the heart and lungs were similar for both (177) Lu-C1P5 and (188) Re-C1P5. The dose to the liver was five times higher for (177) Lu-C1P5. The doses to the tumor were 259 and 181 cGy for (177) Lu-C1P5 and (188) Re-C1P5, respectively. RIT with either (177) Lu-C1P5 or (188) Re-C1P5 was equally effective in inhibiting tumor growth when each was compared to the untreated controls (P = 0.001). On day 5 there was a pronounced staining for gamma H2AX foci in (177) Lu-C1P5 group only and on day 10 it was observed in both (177) Lu-C1P5 and (188) Re-C1P5 groups. (188) Re- and (177) Lu-labeled mAbs were equally effective in arresting the growth of CasKi cervical tumors. Thus, both of these radionuclides are candidates for the clinical trials of this approach in patients with advanced, recurrent or metastatic cervical cancer.
Highlights
In the current era of screening protocols, vaccination strategies and treatment algorithms, infections with human papillomavirus (HPV) should be eradicated
We investigated how the different nuclear decay parameters and chemistries of 188Re and 177Lu influence the efficacy and mechanism of RIT targeting HPV-16/18 E6 oncoprotein in experimental cervical cancer
We started our comparative study of 188Re- and 177Lu- C1P5 monoclonal antibodies (mAbs) with the biodistribution in CasKi tumor- bearing mice
Summary
In the current era of screening protocols, vaccination strategies and treatment algorithms, infections with human papillomavirus (HPV) should be eradicated. HPV-induced cancers express E6 and E7 viral oncogenes which result in lateral expansion and immortalization of infected cells Both oncogenes act to promote cellular proliferation and inhibit apoptosis; E6 oncogene affects the p53 pathway leading to its rapid degradation via the ubiquitin-dependent pathway, whereas E7 binds to the retinoblastoma (pRb) gene causing ineffective regulation of cell growth and deregulation of mitosis [5,6,7]. In our development of the radioimmunotherapy (RIT) approach against HPV-induced malignancies of head and neck and uterine cervical origin, we targeted E6 and E7 oncoproteins expressed in those cancers with E6-or E7-specific monoclonal antibodies (mAbs) tagged to Rhenium-188 (188Re) radioisotope. Consistent and reproducible tumor growth inhibition was noted in murine models of human cervical and head and neck cancers [8,9,10,11,12,13]. The accessibility of intranuclear oncoproteins E6 and E7 to the targeting mAbs is due to the necrosis associated with cellular turnover and release of cellular contents into the interstitial space
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