New study below [1].
The selenium literature suggests that one should not be in the lowest tertial, quartile, quintile ... or even decile, if in the U.S., where wheat consumption does the job for most. But there is no point in aiming higher than the lowest decile. ("Typical dietary intake of selenium in the US is 80 ± 120 ug/day")
In the U.K., which had to switch from Canadian wheat to European wheat when it joined the EU, selenium deficiency/insufficiency is common. In the UK, "the average selenium intake may be as low as 30–40 μg/d" [3].
But what about the SELECT trial - that most expensive & ill-conceived intervention trial? It took a U.S. population that was mostly well-nourished in terms of selenium & gave the intervention arm a supplement regardless of selenium status. This included men who were already supplementing at high levels. There was no exclusion of men who were at or near toxic levels.
Mark Moyad waved a red flag in 2002 [2]:
"Selenium supplements provided a benefit only for those individuals who had lower levels of baseline plasma selenium. Other subjects, with normal or higher levels, did not benefit and may have an increased risk for prostate cancer."
A SELECT-style study might have found selenium to be protective in the UK - or Europe in general.
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Alas, I no longer eat bread regularly. I do have a bottle of sodium selenite in the fridge that I use infrequently. Why that form - isn't it inorganic & not easily taken up? I thought I had an old post on why I will take no other form, but I can't find it. Independently, Nalakrats came to the conclusion that sodium selenite was the way to go.
From the new study:
"Although a large body of data exists from studies of the potential utility of selenium supplementation (using an organic form of selenium) as a chemopreventive strategy, little is known regarding the use of selenium, as inorganic sodium selenite, as a cancer therapy. Our results ... as well as those of other groups .., support the novel idea that selenium in the form of selenite can be used to treat prostate as well as other types of cancer. Importantly, selenite is metabolized differently from organic forms of selenium, with the key difference being that the metabolism of selenite depletes cells of an important antioxidant, glutathione (GSH), and results in the generation of superoxide, a highly reactive and toxic radical that results in the generation of reactive oxygen species (ROS)."
"Our work initially focused on prostate cancer. The rationale for using selenite to treat prostate cancer came from our preclinical studies showing that 1) prostate cancer cells are more sensitive to selenium (sodium selenite)-induced apoptosis than normal prostate epithelial cells, 2) Selenite induces significant growth inhibition of well-established prostate cancer tumors in mice at doses that have no detectable toxicity when administered both ip and po, and 3) Selenite disrupts androgen receptor (AR) signaling, with inhibition of AR expression and activity by selenite occurring via a redox mechanism involving GSH, superoxide, and transcription factor Sp1. Altogether, these findings suggest that selenite may be useful in a variety of potential indications in the natural history of prostate cancer, including both hormone sensitive and hormone refractory prostate cancer, as a single agent, or in combination with radiation, chemotherapy or conventional androgen deprivation therapy (ADT)."
"Given that depletion of GSH is known to have radiosensitizing effects .., and generation of superoxide should enhance the efficacy of radiation-induced ROS, selenite has the potential to sensitize a wide range of tumor types. Our data suggests that selenite-mediated tumor-selective radiosensitization in prostate cancer is due, in part, to differences between MnSOD and Bcl-2 family member expression in tumor vs. normal tissue ... Similar differences in other tumor types, as well as overexpression of Nrf2 and its downstream target genes in cancer .., may also contribute to the differential sensitizing effects of selenite."
"In the Phase 1 trial described here, sodium selenite (given orally at daily doses of 5.5, 11, 16.5, 33 and 49.5 mg) was given concurrently with palliative radiation therapy in patients with metastatic cancer. The primary objective of the study was to assess the safety and tolerability of this combination therapy. Secondary objectives included measurement of pharmacokinetics and evaluation of efficacy. The underlying hypothesis of this study was that the combination of selenite and radiation therapy would be safe and tolerable, and might have the potential to improve PSA responses in the subset of patients with castration-resistant prostate cancer (CRPC) and local response to radiation therapy in patients with metastatic cancer."
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"The primary objective of the study was to assess the safety of this combination therapy. Secondary objectives included measurement of pharmacokinetics (PK) and evaluation of efficacy. Endpoints included assessment of PK, toxicity, tumor response, and pain before and after treatment. The half-life of selenite was 18.5 hours. There were no adverse events attributable to selenite until the 33 mg dose level, at which the primary toxicities were grade 1 GI side effects. One patient treated with 49.5 mg had grade 2 GI toxicity. Although this was not a DLT, it was felt that the highest acceptable dose in this patient population was 33 mg. Most patients had stabilization of disease within the RT fields, with some demonstrating objective evidence of tumor regression. Most patients had a marked improvement in pain and seven out of nine patients with prostate cancer had a decrease in PSA ranging from 11–78%. Doses up to 33 mg selenite were well tolerated in combination with RT. A randomized, well controlled study is needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative RT."
-Patrick
[1] Full Text: sciencedirect.com/science/a...
Discussion
Given the promising results with inorganic sodium selenite in preclinical tumor models and some early clinical trials, there is increasing interest in using selenite as a cytotoxic agent, and/or as a sensitizer. For example, in a study of newly diagnosed patients with non-Hodgkin's lymphoma treated with standard chemotherapy with or without adjuvant sodium selenite (0.2 mg/kg per day for 30 days), the patients receiving selenite had down-regulated levels of Bcl-2 and improved clinical outcomes [11]. In another study of selenite (0.2 mg/kg per day for 7 days) in combination with chemotherapy, addition of selenite resulted in a significant increase in the percentage of apoptotic lymphoma cells and clinical response compared to patients treated with chemotherapy alone [12]. Sodium selenite has also been studied in a variety of other tumor types, including colon cancer [13], and head and neck cancer [14]. In addition, patients with multiple tumor types were enrolled in a Phase one trial: the SECAR study, in which 34 patients with different resistant tumor types received i.v. sodium selenite daily for 5 consecutive days either for 2 or 4 weeks [15]. The MTD was defined as 10.2 mg/m2 with a calculated median plasma half-life of 18.25 hours. The most common side effects were fatigue, nausea and cramps in fingers and legs [15].
While there have been no clinical trials to date studying sodium selenite as a potential radiosensitizer, a randomized Phase three trial studied the ability of selenium to function as a radioprotector of normal tissues presumed to be secondary to enhanced antioxidant capacity, as organic selenium is used for the synthesis of antioxidant enzymes. This trial compared selenium supplementation (500 μg po on days of radiation therapy and 300 μg on days without radiation) with observation in patients with gynecologic malignancies treated with radiation therapy [16]. Interestingly, there was a reduction in the number of episodes and severity of radiation-induced diarrhea. Of note, this study utilized relatively low doses of an organic form of selenium, which is metabolized differently from inorganic forms, for purposes of protection rather than sensitization.
More relevant to our study, is the study by Corcoran et al. [17], using the inorganic form of selenium, sodium selenate (SeO4-, which is not as reactive with thiols as selenite, SeO32-). In this study, patients with castration-resistant prostate cancer received escalating doses of selenate orally. The MTD was 60 mg daily. Dose limiting toxicity (fatigue and diarrhea) occurred at 90 mg daily, with no grade 4 toxicity. One patient treated with 60 mg/day had a PSA response greater than 50% for 11 weeks, and the mean PSA doubling time nearly doubled in patients following treatment.
Given that sodium selenite depletes GSH and generates superoxide radicals when metabolized, it has the potential to radiosensitize multiple tumor types. Since in our preclinical studies, it radiosensitized tumors in vivo and did not sensitize GI epithelium to radiation (in fact it had a slight protective effect), it has the theoretical potential to significantly increase the therapeutic window for radiation therapy. This and other preclinical data to date, as well as early clinical data for other indications, provided a compelling rationale for the study of sodium selenite in combination with radiation therapy. In the study described here, the safety, tolerability and PK of sodium selenite was studied in 15 patients with advanced/metastatic tumors receiving concurrent sodium selenite with palliative radiation therapy. The 33 mg dose level had acceptable tolerability, with the primary toxicity being grade 1 GI side effects. These side effects were well controlled with ondansetron and loperamide-Hcl prn. It was concluded that 33 mg would be a reasonable dose for future studies when given orally, one time per day, with no oral intake for at least 2 hours prior.
The half-life obtained from the parameter estimates of the PK model is in agreement with what is reported in the literature. The SECAR study reported a median half-life of approximately 18 hours in patients with malignant disease receiving IV sodium selenite as a single agent [15]. Corcoran et al. noted significant accumulation of selenite, the active metabolite of selenate, following selenate administration in male patients diagnosed with castrate-resistant prostate cancer [17]. The PK model we have developed for this study captures the accumulation of selenite and appropriately characterizes the sparse data and variability in the patient population.
From the simulations for the PK model, it takes approximately 1 day to enter the desired therapeutic range for the 11 mg dose level when given twice daily. While a few dosing regimens are possible, 11 mg was chosen to minimize nausea.
Efforts were made to assess potential efficacy signals. Given the inherent limitations of small numbers, and the heterogeneous patient population in terms of tumor type, site of irradiation, radiation dose/fractionation, prior and concurrent systemic therapies, and lack of randomization, it is not possible to draw any definitive conclusions. Nevertheless, the majority of patients with prostate cancer did exhibit a decrease in PSA following treatment, and the majority of patients on the study had a decrease in pain indices. Lastly, the majority of patients had stabilization of disease within the radiation therapy field(s), with some demonstrating objective evidence of tumor regression. Similar findings can be observed in patients treated with radiation therapy without selenite, and a randomized, well controlled, study will be needed at the 33 mg dose level to determine if selenite results in clinically meaningful improvements in the response to palliative radiation therapy.
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