Effect of Tumor Targeted-Anthracycline Nanomedicine, HPMA Copolymer-Conjugated Pirarubicin (P-THP) against Gynecological Malignancies

Anthracyclines are important for the treatment of gynecological malignancies, but their effects are modest, and one of the major reasons is the lack of a tumor-targeting property. To overcome this drawback, a poly (hydroxypropyl meta-acrylamide) conjugated with tetrahydropyraryl doxorubicin (P-THP) has been developed, which exhibits a highly tumor-specific accumulation owing to the enhanced permeability and retention effect. The effect of P-THP has been confirmed by using various cell lines and solid tumor models, while its effect on gynecological malignancies have not been investigated. In this regard, human uterine sarcoma cell line with metastatic potential MEA-SA C9 high, epithelial ovarian cancer cell line A2780 and its cisplatin-resistant line A2780cis, and DOX-resistant line A2780ADR were used in this study, and the therapeutic effect as well as the safety profiles of P-THP were investigated compared to native THP, cisplatin, and paclitaxel, which are commonly used for gynecological malignancies, both in vitro and in vivo. Similar to native THP, a dose-dependent toxicity of P-THP was identified in all cell lines. Moreover, the IC50 values in the 3 h following P-THP were 1.5–10 times higher than those at 72 h, though the intracellular uptake of P-THP in all cells were 2–10-fold less than THP. In vivo studies using xenograft tumor models revealed that P-THP significantly suppressed the MES-SA C9 high, A2780, and A2780cis tumor growth at the dose of 15 mg/kg (THP equivalent), which is three times above the maximal tolerance dose of native THP, while no body weight loss or acute death occurred. However, in A2780ADR cells and the xenograft model, no significant difference in the therapeutic effect was observed between THP and P-THP, suggesting that P-THP exhibits its effect depending on the release of the active free THP in tumor tissues, and thus the internalization into tumor cells. These findings indicates that P-THP has the potential as a therapeutic for gynecological malignancies to improve the therapeutic outcomes and survival rates of patients, even in refractory patients

Clinical management of uterine cervical mullerian adenosarcoma: A clinicopathological study of six cases and review of the literature

Objective: To assess the clinicopathological characteristics and clinical management of patients diagnosed with mullerian adenosarcoma of the uterine cervix. Materials and methods: Records of six patients surgically treated for cervical mullerian adenosarcoma were reviewed. Results: The median age of the patients was 50 years (range, 17–74). Four patients presented with vaginal bleeding and two of them had watery discharge as the primary symptoms. Three nulliparous patients who hoped to preserve their uterus were included in this study and only one of the three patients received fertility-preservation surgery. Five patients underwent hysterectomy (simple in 3, modified radical in 2) with bilateral salpingo-oophorectomy or bilateral salpingectomy. One patient underwent conization of the cervix to preserve her fertility as there was no sarcomatous overgrowth, heterologous elements, or deep cervical stromal invasion. A recurrence of cervical mullerian adenosarcoma with sarcomatous overgrowth was observed in one patient who underwent simple hysterectomy. Conclusion: The presence of sarcomatous overgrowth and deep cervical stromal invasion are associated with poor prognosis. Along with adequate counseling, fertility-preservation surgery may be an acceptable option for exophytic cervical mullerian adenosarcoma in the cases that do not show sarcomatous overgrowth and deep cervical stromal invasion. Keywords: Clinicopathological characteristics, Fertility-preservation surgery, Mullerian adenosarcoma, Uterine cervi