Evaluation of cytotoxic effects of a peritoneal membrane for chemotherapeutic drug delivery in ovarian cancer

• Grant number: 20/11698-2
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2021
• End date: September 30, 2023
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Maria Lucia Hirata Katayama
• Grantee: Maria Lucia Hirata Katayama
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). Coordenadoria de Serviços de Saúde (CSS). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Ademar Benévolo Lugão ; Helena Passarelli Giroud Joaquim Nadal ; Marcelo Simonsen ; Maria Aparecida Azevedo Koike Folgueira

Abstract

Introduction: Ovarian cancer is the most lethal gynecological cancer and despite scientific advances in recent decades, platinum compounds remain the basis of chemotherapy, albeit with high rates of recurrence. The different forms of application of intracavitary chemotherapy have clinical benefits, but considerable toxicity that sometimes limits or annuls the advantage of treatment in loco. It is necessary to evaluate alternative ways for intraperitoneal administration of chemotherapy, associated with fewer side effects. In the present study, we will investigate a new form of administration to deliver peritoneal chemotherapy by means of a membrane which slowly releases cysplatin. With this device, we aim to decrease the therapeutic toxicity and optimize the response of the tumor tissue to continuous and direct exposure to the drug. Methodology: The membrane will be built with electrophilic polymerization of polyvinyl alcohol and agar. Different concentrations of cysplatin will be incorporated into the membrane and cytotoxicity will be tested on ovarian carcinoma strains, including SKVO3 in vitro. After determining the ideal concentration of the chemotherapeutic drug, an animal study will be carried out: mice with peritoneal xenograft of SKVO3 cells will be subjected to randomization into 4 groups: surgery to implant the peritoneal membrane containing cysplatin, surgery for the implantation of the peritoneal membrane without the drug, administration of free intraperitoneal cysplatin and no treatment. The neoplastic dissemination will be quantified by weekly bioluminescence, and organs will be evaluated for metastatic dissemination and tumor measurement during autopsy. The expression of cell proliferation and apoptosis markers by immunohistochemistry will also be evaluated: Ki67, CD-31, caspase-3 (CASP3), and marking of terminal breaks with dUTP and deoxynucleotidyl transferase (TUNEL reaction) of the tumor sample. Clinical toxicity will be assessed by weight loss and inactivity, and the concentration of serum and organ cisplatin will be assessed at the time of sacrifice by liquid chromatography. Expected outcome: We aim to develop a membrane impregnated with cysplatin with satisfactory therapeutic potential for treating ovarian cancer in mice. We expect the tumor concentration of cysplatin to be higher in organs, such as the liver and kidneys, reducing the potential for toxicity. We believe that the slow release of cysplatin from the peritoneal membrane can minimize the high toxicity currently related to on-site treatment in humans. (AU)