Phase I trial of selenium plus chemotherapy in gynecologic cancers.

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-naïve 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.

A Model of the Development of Cisplatin Resistance in Human Small Cell Lung Cancer Xenografts.

BACKGROUND/AIM: To study the prevention of chemotherapy resistance, we have previously designed models of drug-resistant ovarian cancer. We here report an in vivo model of cisplatin-resistant small cell lung cancer (SCLC). MATERIALS AND METHODS: Mice bearing H526 SCLC xenografts received intraperitoneal pretreatment with a sub-effective cisplatin dose (0.75-1.5 mg/kg) or no pretreatment (controls). Seven days later, all mice received a higher cisplatin dose (3.0 mg/kg), and tumor response was recorded. Cell cultures initiated from pretreated and control xenografts were tested for cisplatin resistance and for glutathione-S-transferase (GST) activity. RESULTS: Pretreatment with 1.5 mg/kg cisplatin induced resistance to 3.0 mg/kg cisplatin. Cells from a pretreated tumor were cisplatin resistant and had nearly twice the GST activity as cells from a control tumor. CONCLUSION: Such cells may prove useful for identifying other resistance mechanisms and thus guide the selection of potential preventative agents to be tested in the in vivo model.

Prevention of carboplatin-induced resistance in human ovarian tumor xenografts by selenite.

BACKGROUND/AIM: We have been exploring a prevention approach to the problem of drug resistance which develops during ovarian cancer chemotherapy. We have previously described an in vivo model of the development of resistance to the chemotherapy drug cisplatin in xenografts, and the prevention of this resistance by selenium compounds. However, a different platinum-based drug, carboplatin, is frequently utilized in ovarian cancer treatment. The aim of the present study was to design a model for the induction of resistance by carboplatin in vivo. MATERIALS AND METHODS: Tumors were initiated in immunodeficient mice by subcutaneous inoculation of A2780 human ovarian tumor cells. The sensitivity of the resulting tumors to therapy was determined by measuring the effect on tumor growth of a single intraperitoneal (i.p.) treatment with a high dose of carboplatin. RESULTS: The growth of control tumors was completely (although temporarily) stopped by this treatment; however, a single pre-treatment with a low i.p. dose of carboplatin resulted in the rapid development of resistance to carboplatin, and cross-resistance to cisplatin. Pre-treatment with selenite in addition to carboplatin prevented the induction of resistance. When cells from these pre-treated tumors were transplanted to new animals, the derivative tumors retained the sensitive or resistant phenotype of their tumor of origin. CONCLUSION: Selenite can prevent the induction of resistance by carboplatin in human ovarian tumors, and thus may offer an approach to extending the long-term efficacy of platinum chemotherapy.

Selenite enhances and prolongs the efficacy of cisplatin treatment of human ovarian tumor xenografts.

BACKGROUND/AIM: Our earlier studies on ovarian tumor xenografts provide evidence that co-treatment with selenite prevents the development of resistance to single-treatment using the drug cisplatin. However, these studies did not reflect the repetitive schedule of clinical chemotherapy. We hypothesized that selenite can enhance the effectiveness of cisplatin during the course of repeated treatments, reflecting clinical practices. MATERIALS AND METHODS: Multiple i.p. injections of cisplatin (5.2 mg/kg) alone, or with selenite (1.5 mg/kg), were administered to mice bearing subcutaneous xenografts of human ovarian tumor (A2780) cells and the tumor volume was recorded. RESULTS: Selenite increased and prolonged the efficacy of multiple cisplatin treatments, although selenite was not an effective inhibitor by itself. In the absence of selenite, the effectiveness of cisplatin decreased. CONCLUSION: The ability of selenite to prolong the effectiveness of repetitive cisplatin treatment, most likely by preventing the development of resistance, makes it a strong candidate for inclusion in clinical trials.