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Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy.

ABSTRACT: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The major cause of EOC's lethality is that intraperitoneal recurrence occurs with high frequency due to occult metastasis. We had demonstrated that plasma-activated medium (PAM) exerts a metastasis-inhibitory effect on ovarian cancer in vitro and in vivo. Here we investigated how PAM inhibits intraperitoneal metastasis. We studied PAM's inhibition of micro-dissemination onto the omentum by performing in vivo imaging in combination with a sequential histological analysis. The results revealed that PAM induced macrophage infiltration into the disseminated lesion. The iNOS-positive signal was co-localized at the macrophages in the existing lesion, indicating that PAM might induce M1-type macrophages. This may be another mechanism of the antitumor effect through a PAM-evoked immune response. Intraperitoneal lavage with plasma-activated lactate Ringer's solution (PAL) significantly improved the overall survival rate in an ovarian cancer mouse model. Our results demonstrated the efficiency and practicality of aqueous plasma for clinical applications.

SUBMITTER: Nakamura K

PROVIDER: S-EPMC7962102 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy.

Nakamura Kae K Yoshikawa Nobuhisa N Mizuno Yuko Y Ito Miwa M Tanaka Hiromasa H Mizuno Masaaki M Toyokuni Shinya S Hori Masaru M Kikkawa Fumitaka F Kajiyama Hiroaki H

Cancers 20210307 5

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The major cause of EOC's lethality is that intraperitoneal recurrence occurs with high frequency due to occult metastasis. We had demonstrated that plasma-activated medium (PAM) exerts a metastasis-inhibitory effect on ovarian cancer in vitro and in vivo. Here we investigated how PAM inhibits intraperitoneal metastasis. We studied PAM's inhibition of micro-dissemination onto the omentum by performing in vivo imaging in co ...[more]

PMID: 33799991

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Project description:Artemisinin (ARS) and its derivatives, which are clinically used antimalarial agents, have shown antitumor activities. Their therapeutic potencies, however, are limited by their low solubility and poor bioavailability. Here, through a pharmacophore hybridization strategy, we synthesized ARS-drug conjugates, in which the marketed chemotherapeutic agents chlorambucil, melphalan, flutamide, aminoglutethimide, and doxifluridine, were separately bonded to Dihydroartemisinin (DHA) through various linkages. Of these, the artemisinin-melphalan conjugate, ARS4, exhibited most toxicity to human ovarian cancer cells but had low cytotoxicity to normal cells. ARS4 inhibited the growth and proliferation of ovarian cancer cells and resulted in S-phase arrest, apoptosis, and inhibition of migration; these effects were stronger than those of its parent drugs, DHA and melphalan. Furthermore, ARS4 modulated the expression of proteins involved in cell cycle progression, apoptosis, and the epithelial-mesenchymal transition (EMT). Moreover, in mice, ARS4 inhibited growth and intraperitoneal dissemination and metastasis of ovarian cancer cells without observable toxic effects. Our results provide a basis for development of the compound as a chemotherapeutic agent.Research in contextArtemisinin compounds have recently received attention as anticancer agents because of their clinical safety profiles and broad efficacy. However, their therapeutic potencies are limited by low solubility and poor bioavailability. Here, we report that ARS4, an artemisinin-melphalan conjugate, possesses marked in-vitro and in-vivo antitumor activity against ovarian cancer, the effects of which are stronger than those for its parent drugs, Dihydroartemisinin and melphalan. In mice, ARS4 inhibits localized growth of ovarian cancer cells and intraperitoneal dissemination and metastasis without appreciable host toxicity. Thus, for patients with ovarian cancer, ARS4 is a promising chemotherapeutic agent.

Project description:ObjectiveThe aim of this study was to assess the safety and efficacy of extending bevacizumab therapy beyond 15 months in nonprogressive ovarian cancer.Patients and methodsIn this multinational prospective single-arm study (ClinicalTrials.gov NCT01239732), eligible patients had International Federation of Gynecology and Obstetrics stage IIB to IV or grade 3 stage I to IIA ovarian cancer without clinical signs or symptoms of gastrointestinal obstruction or history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the preceding 6 months. Prior neoadjuvant chemotherapy was permitted. After debulking surgery, patients received bevacizumab 15 (or 7.5) mg/kg every 3 weeks (q3w) with 4 to 8 cycles of paclitaxel (investigator's choice of 175 mg/m q3w or 80 mg/m weekly) plus carboplatin AUC 5 to 6 q3w. Single-agent bevacizumab was continued until progression or for up to 24 months. The primary end point was safety.ResultsBetween December 2010 and May 2012, 1021 patients from 35 countries began study treatment. Bevacizumab was administered at 15 mg/kg in 89% of patients and for more than 15 months in 53%. Median follow-up duration was 32 months (range, 1-50 months). The most common all-grade adverse events were hypertension (55% of patients), neutropenia (49%), and alopecia (43%). The most common grade 3 or higher-grade adverse events were neutropenia (27%) and hypertension (25%). Bevacizumab was discontinued because of proteinuria in 5% of patients and hypertension in 3%. Median progression-free survival (PFS) was 25.5 months (95% confidence interval, 23.7-27.6 months).ConclusionExtended bevacizumab demonstrated increased incidences of proteinuria and hypertension compared with 12 or 15 months of bevacizumab in previous trials, but these rarely led to bevacizumab discontinuation. Median PFS is the longest reported for frontline bevacizumab-containing therapy. The longer bevacizumab duration beyond 15 months in this study may improve PFS without substantially compromising safety.

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Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy.

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Preclinical Verification of the Efficacy and Safety of Aqueous Plasma for Ovarian Cancer Therapy.

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