Phase I trial of selenium plus chemotherapy in gynecologic cancers

Autor: Lorna Rodriguez-Rodriguez, Paula B. Caffrey, Muthu N. Kumaran, Mira Hellmann, Wilberto Nieves-Neira, Brian Buckley, Michael P. Kane, Murugesan Gounder, Darlene Gibbon, Gerald D. Frenkel, Mihae Song, Weichung Shih, Ami Vaidya
Rok vydání: 2018
Předmět:
0301 basic medicine
Lung Diseases
medicine.medical_treatment
Gene Expression
Selenious Acid
Gastroenterology
Carboplatin
chemistry.chemical_compound
0302 clinical medicine
Antineoplastic Combined Chemotherapy Protocols
Chemotherapy-Induced Febrile Neutropenia
Ovarian Neoplasms
Obstetrics and Gynecology
food and beverages
RNA-Binding Proteins
Middle Aged
DNA-Binding Proteins
Oncology
Paclitaxel
030220 oncology & carcinogenesis
Female
Adult
medicine.medical_specialty
Maximum Tolerated Dose
chemistry.chemical_element
Down-Regulation
Breast Neoplasms
Neutropenia
Infections
Article
03 medical and health sciences
Selenium
Pharmacokinetics
Internal medicine
Cell Line
Tumor
Selenoprotein P
medicine
Humans
Response Evaluation Criteria in Solid Tumors
Aged
Chemotherapy
Glutathione Peroxidase
business.industry
medicine.disease
030104 developmental biology
chemistry
Nervous System Diseases
business
Febrile neutropenia
Zdroj: Gynecologic oncology. 150(3)
ISSN: 1095-6859
Popis: Purpose Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. Methods Chemo-naive patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. Results Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 μg to 5000 μg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. Conclusion Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 μg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.
Databáze: OpenAIRE
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