A multinational phase 2 study of nanoliposomal irinotecan sucrosofate (PEP02, MM-398) for patients with gemcitabine-refractory metastatic pancreatic cancer.

BACKGROUND: PEP02, also known as MM-398, is a novel nanoliposomal irinotecan that has improved pharmacokinetics and tumour bio-distribution of the free drug. This phase 2 study evaluated PEP02 monotherapy as second-line treatment for pancreatic cancer. METHODS: Patients who had metastatic pancreatic adenocarcinoma, Karnofsky performance status ≥70, and had progressed following gemcitabine-based therapy were eligible. Intravenous injection of PEP02 120 mg m(-2) was given every 3 weeks. Simon 2-stage design was used. The primary objective was 3-month survival rate (OS(3-month)). RESULTS: A total of 40 patients were enrolled. The most common severe adverse events included neutropenia, abdominal pain, asthenia, and diarrhoea. Three patients (7.5%) achieved an objective response, with an additional 17 (42.5%) demonstrating stable disease for a minimum of two cycles. Ten (31.3%) of 32 patients with an elevated baseline CA19-9 had a >50% biomarker decline. The study met its primary end point with an OS(3-month) of 75%, with median progression-free survival and overall survival of 2.4 and 5.2 months, respectively. CONCLUSION: PEP02 demonstrates moderate antitumour activity with a manageable side effect profile for metastatic, gemcitabine-refractory pancreatic cancer patients. Given the limited treatment options available to this patient population, a phase 3 trial of PEP02 (MM-398), referred to as NAPOLI-1, is currently underway.

A phase 1 trial of imatinib, bevacizumab, and metronomic cyclophosphamide in advanced colorectal cancer.

BACKGROUND: This phase 1 clinical trial was conducted to determine the safety, maximum-tolerated dose (MTD), and pharmacokinetics of imatinib, bevacizumab, and metronomic cyclophosphamide in patients with advanced colorectal cancer (CRC). METHODS: Patients with refractory stage IV CRC were treated with bevacizumab 5 mg kg(-1) i.v. every 2 weeks (fixed dose) plus oral cyclophosphamide q.d. and imatinib q.d. or b.i.d. in 28-day cycles with 3+3 dose escalation. Response was assessed every two cycles. Pharmacokinetics of imatinib and cyclophosphamide and circulating tumour, endothelial, and immune cell subsets were measured. RESULTS: Thirty-five patients were enrolled. Maximum-tolerated doses were cyclophosphamide 50 mg q.d., imatinib 400 mg q.d., and bevacizumab 5 mg kg(-1) i.v. every 2 weeks. Dose-limiting toxicities (DLTs) included nausea/vomiting, neutropaenia, hyponatraemia, fistula, and haematuria. The DLT window required expansion to 42 days (1.5 cycles) to capture delayed toxicities. Imatinib exposure increased insignificantly after adding cyclophosphamide. Seven patients (20%) experienced stable disease for >6 months. Circulating tumour, endothelial, or immune cells were not associated with progression-free survival. CONCLUSION: The combination of metronomic cyclophosphamide, imatinib, and bevacizumab is safe and tolerable without significant drug interactions. A subset of patients experienced prolonged stable disease independent of dose level.

Pancreatic cancer treatment and research: an international expert panel discussion.

BACKGROUND: Pancreatic cancer has proven extremely challenging to treat. A collaborative effort is needed to advance research and improve treatment. An expert conference was conducted to elicit perspectives regarding the current treatment and future research of pancreatic cancer. METHODS: The conference comprised an international panel of experts representing five European countries and the United States. RESULTS: Adjuvant radiotherapy is used more frequently in the United States than in Europe. In locally advanced disease, there is now more emphasis on early chemotherapy in both Europe and the United States. In metastatic disease, combination chemotherapy is commonly used in Europe and the United States. This varies by country. Advancing pancreatic research will require improving biorepositories and developing a roadmap to prioritize therapeutic targets in different models. Small randomized phase II trials of both non-selected and enriched patient populations will help identify activity of new agents. Phase III trials should only be initiated in appropriate patients based on strong clinical and biological signals. Developing drugs in the adjuvant setting may be preferable to eliminate some of the challenges of drug development in the advanced disease setting. CONCLUSION: Progress in research combined with encouraging improvements from the past offer hope for the future of pancreatic cancer patients.

Chemoprevention of mouse colon tumors with difluoromethylornithine during and after carcinogen treatment.

alpha-Difluoromethylornithine (DFMO) treatment has been shown to modify carcinogenesis in many experimental tumor models, including skin, breast, and colon. This study was designed to determine whether DFMO treatment can inhibit experimental mouse colon tumors after carcinogen treatment and whether an associated effect of DFMO on cell proliferation in colon mucosa occurs. Male CD1 mice (40 per group) received dimethylhydrazine (30 mg/kg/week x 6 weeks, s.c.) and various schedules of DFMO, 1% in drinking water: Group A, none; Group B, following dimethylhydrazine treatment; Group C, during dimethylhydrazine treatment; and Group D, continuously throughout the study. Measurements of RBC polyamine levels showed that DFMO treatment ablated putrescine levels and confirmed that a systemic biological effect was achieved. Analysis of tumor data showed a significant inhibitory effect of DFMO treatment on colon tumor (adenomas and adenocarcinomas) incidence in Groups B (24%) and D (20%) compared to control Group A (52%, P less than 0.05 A versus B, P less than 0.02 A versus D) and on squamous cell carcinomas of the anus in all groups (P less than 0.001 A versus B, P less than 0.05 A versus C, A versus D). No consistent effect of DFMO treatment on cell proliferation in colon mucosa was identified. This study supports the hypothesis that DFMO treatment alters events in the postinitiation phases of mouse colon tumorigenesis.

Correlative study on expression of CA 19-9 and DU-PAN-2 in tumor tissue and in serum of pancreatic cancer patients.

The serum levels of CA 19-9 and DU-PAN-2 antigens and their expression in tumor tissue were examined in 22 pancreatic cancer patients and the results were correlated with the Lewis (Le) blood group phenotypes of the individuals. In tumor tissue, CA 19-9 was expressed in 17 of 22 (77%) specimens. The negative cases included three patients with Lea-b-, one with Lea+b- and the other with Lea-b+ phenotypes. DU-PAN-2 antigen was expressed in 20 of 22 (91%) cancer tissues. The two DU-PAN-2-negative cases were CA 19-9-positive. The combination of two markers increased the sensitivity to 100%. In the serum, CA 19-9 level was elevated (greater than 37 U/ml) in 16 of 21 (73%) cases. All Lea-b- patients had values less than 37 U/ml. An elevated level of DU-PAN-2 (greater than 300 U/ml) was detected in 14 of 21 (67%) patients including three cases with Lea-b- type. In only one patient were both antigens below the cutoff levels so that the combination of two biomarkers elevated the sensitivity to 95%. The study indicated that the cocktail of 19-9 and DU-PAN-2 antibodies might increase the sensitivity and specificity for clinical diagnosis of pancreatic cancer. In 19 of 21 (90%) cases, the serum CA 19-9 level correlated with the expression of the antigen in the cancer tissue. Discrepancy was seen in two cases; one patient had an elevated level of CA 19-9 in the serum, but lacked this antigen in the cancer cells. In the second case, the situation was reversed. For DU-PAN-2, positive correlation was seen in 14 of 21 (67%) cases. Six of seven patients with low DU-PAN-2 levels expressed the antigen in their tumor cells, and one patient with DU-PAN-2-negative cancer tissue had an elevated level of this marker in the serum. Thus, CA 19-9 expression in serum corresponded more closely to expression in tissue than did that of DU-PAN-2 antigen. The serum levels of these antigens, however, is likely due to multiple factors, only one of which is the qualitative and quantitative expression of the antigens in tumors.

Relationship of carbohydrate antigen 19-9 and Lewis antigens in pancreatic cancer.

Carbohydrate antigen (CA) 19-9 identified by a murine monoclonal antibody against a colorectal carcinoma antigen is thought to be a sialylated Lewis (Le)a blood group antigen and occurs in high concentration in serum of patients with pancreatic carcinoma. This study was designed to identify the relationship between Lewis antigens and CA 19-9 in patients with pancreatic cancer. The following analyses were performed in 20 pancreatic cancer patients: Lea and Leb antigen phenotype in saliva (modified enzyme-linked immunosorbent assay) or on red cells (hemagglutination); CA 19-9 levels (radioimmunoassay) in serum; and CA 19-9 and Lea and Leb expression (immunoperoxidase assay) on tumor tissue. Lea-b- patients based on salivary phenotype failed to express CA 19-9 in tumor tissue and had normal or low levels of CA 19-9 (less than 37 units/ml) in serum (P = 0.0011, versus Lea+b- and Lea-b+ patients). Eighty-eight % of Lea+b- and Lea-b+ patients had elevated serum CA 19-9 levels (greater than 37 units/ml). All Lea+b- and Lea-b+ patients expressed both Lea and Leb antigens in tumor tissue. These results support the view that Lea-b- pancreatic cancer patients cannot manufacture CA 19-9. Surprisingly, Lea-positive patients express Leb antigen in tumor tissue; in this subgroup, Leb antigen may be a tumor-specific biomarker.

Unconjugated bilirubin inhibits in vitro cytotoxic T lymphocyte activity of human lymphocytes.

Septic complications have been major problems in the management of patients with obstructive jaundice and neonatal jaundice. This study investigates effects bilirubin on human T lymphocyte responses against allogeneic mixed lymphocyte reaction. In vitro exposure of human peripheral blood mononuclear cells (PBMNC) with unconjugated bilirubin at pathological levels (6 to 12 mg/dl) did not alter the subsets of CD3, CD4, CD8, CD14, CD19 and CD56 positive populations, or expression of costimulatory surface molecules CD2, CD3, CD4 and CD8. Further incubation of bilirubin-treated PBMNC with irradiated B lymphoid Raji cells after removal of the extracellular bilirubin resulted in a dose-dependent decrease of cytotoxic T lymphocyte (CTL) activity, DNA synthesis, and expression of Tac antigen (CD25) and transferrin receptor (CD71). However, no significant change of interleukin-2 (IL-2) production was observed after this incubation between bilirubin-treated and -untreated PBMNC. These results suggest that bilirubin inhibits the induction of CTL activity, and this defect may result from the impaired responsiveness against IL-2. These observations may help explain the increased infection observed in hyperbilirubinemic patients.

Unconjugated bilirubin inhibits in vitro major histocompatibility complex-unrestricted cytotoxicity of human lymphocytes.

Septic complications have been major problems in the management of patients with obstructive jaundice and neonatal jaundice. This study investigates effects of unconjugated bilirubin on lymphocyte-mediated cytotoxicity against human tumor target cells. In vitro exposure of human peripheral blood lymphocytes (PBL) with bilirubin IX alpha in bovine albumin solution resulted in a dose-dependent decrease of both natural killer activity and antibody dependent cellular cytotoxicity (ADCC) activity. Inhibition of both activities correlated with the amounts of intracellular bilirubin. Expression of cell surface CD16, CD56 antigen, and IL-2 receptor beta chain was unchanged in bilirubin-treated PBL as compared to bilirubin-untreated PBL. When bilirubin-treated PBL were cultured with interleukin-2 (IL-2), a dose-dependent decrease of lymphokine-activated killing activity, ADCC activity, and DNA synthesis was observed. Expression of CD56 antigen and IL-2 receptor alpha chain was unchanged in bilirubin-treated PBL following IL-2 stimulation as compared to bilirubin free control. These results suggest that bilirubin inhibits major histocompatibility complex-unrestricted cytotoxicity in both unstimulated and IL-2 stimulated lymphocytes. These observations may help explain the increased susceptibility to infection observed in hyperbilirubinemic patients.

The value of hepatic ultrasound and biochemical liver tests in screening for liver metastases.

The records of 92 patients with a known diagnosis of extrahepatic cancer who had undergone hepatic ultrasound, biochemical liver tests (alkaline phosphatase, SGOT, lactic dehydrogenase, and bilirubin levels), and subsequent liver biopsy or autopsy within a 6-week period were reviewed. The sensitivity, specificity, and accuracy of the ultrasound and biochemical tests in the detection of metastatic liver disease were calculated. Although there was no significant difference in the sensitivity of either examination, the ultrasound demonstrated higher specificity and accuracy than the biochemical liver tests. The high sensitivity of hepatic ultrasound prevailed even in patients with normal biochemical liver tests. The sensitivity of hepatic ultrasound was significantly lower in patients with lymphoma compared with patients with colorectal cancer (50% v 100%, P less than .05). Notable incidental extrahepatic findings were reported in 25% of the ultrasound examinations. In institutions skilled in sonography, hepatic ultrasound may be a superior tool in the detection of liver metastases in most solid tumors, excluding lymphoma, and offers the additional advantage of simultaneous biliary tract and perihepatic visualization.

Phase II trial of interferon gamma and monoclonal antibody 17-1A in pancreatic cancer: biologic and clinical effects.

Thirty patients with advanced measurable pancreatic adenocarcinoma were entered onto a phase II trial with recombinant interferon gamma (Biogen, Cambridge, MA; 10(6) U/m2 daily for 4 days) and monoclonal antibody (Mab) 17-1A (Centocor, Malvern, PA; 150 mg in autologous leukocytes on days 2, 3, and 4 following interferon infusion). The effect of a single interferon gamma treatment on natural and antibody-dependent cellular cytotoxicity (ADCC), Fc receptor occupancy by antibody, and human leukocyte antigen-DR (HLA-DR) expression on monocytes and lymphocytes was also studied. Toxicity was modest and generally limited to grade I to II fever, nausea and vomiting, and hepatotoxicity. Five patients were considered to be nonassessable for response. Of the 25 assessable patients, one objective response (complete remission for a duration of 4 months) was observed. Stable disease for 2 months or greater was noted in nine patients. The median survival for the group was 5 months. Analysis of cytotoxicity data obtained prior to treatment showed reduced natural cytotoxic activity in these patients compared with normal volunteers. A significant improvement in natural cytotoxic activity to normal levels occurred within 24 hours following the interferon gamma infusion. This was also associated with augmented antibody-dependent cellular cytotoxicity. Although HLA-DR expression was not increased on either monocytes or lymphocytes, an increased capacity of both lymphocytes and monocytes to bind Mab 17-1A was observed. In all in vitro assays of ADCC, the presence of antibody excess was associated with improved cytolytic activity. In spite of the favorable modulation of cytolytic activity and improved ability of effector cells to bind Mab, we failed to demonstrated adequate clinical efficacy in the treatment of patients with pancreatic adenocarcinoma using this dose and schedule of interferon gamma and Mab 17-1A. Future trials will focus on alternate schedules of Mab 17-1A with the hope of improving tumor antigen saturation and circulating levels of infused antibody.

Characterization of bilirubin transport system by human peripheral blood mononuclear cells.

Decreased immune responses have been observed in hyperbilirubinemic patients. This study investigates bilirubin transport into human peripheral blood mononuclear cells (PBMNCs). In vitro incubation of PBMNCs at 37 degrees C with 0-12 mg/dl bilirubin in solution with a fixed bovine serum albumin (BSA) concentration (3.0 g/dl) resulted in a dose-dependent increase of intracellular bilirubin in both monocytes and lymphocytes. Bilirubin uptake in monocytes was significantly higher (up to 2.7 times) than in lymphocytes under the same culture conditions. When PBMNCs were incubated with varying concentrations of bilirubin (0-16 mg/dl) in fixed BSA (3.0 g/dl) solution or at a fixed bilirubin/albumin molar ratio (0.4), the initial velocity of uptake in both cell fractions was proportional to the free (unbound to albumin) bilirubin concentration rather than the total bilirubin concentration. Bilirubin uptake by both cell fractions was significantly inhibited by treatment with metabolic inhibitors. Bilirubin uptake by monocytes continued to increase in parallel with incubation temperature from 0 degrees C to 40 degrees C, whereas uptake by lymphocytes reached a maximal level at 20 degrees C and remained constant thereafter. These results suggest that monocytes and lymphocytes incorporate bilirubin in proportion to the free bilirubin concentration and this function may rely on different energy-dependent mechanisms.

The effect of garlic extract on human metabolism of acetaminophen.

Several studies suggest that the constituents of garlic may inhibit experimentally induced carcinogenesis. To evaluate the chemopreventive properties of garlic in humans, the effects of chronic administration of an aged garlic extract on the disposition of acetaminophen and metabolites were studied. This commonly used drug was chosen because it forms a reactive electrophilic metabolite after oxidative metabolism. Sixteen subjects ingested daily doses of garlic extract (approximately equivalent to six to seven cloves of garlic) for 3 months. Before the course of garlic, at the end of each month and 1 month after termination of garlic administration, a 1-g oral dose of acetaminophen was given to each subject. Plasma and urine were measured for acetaminophen and the glucuronide, sulfate, cysteinyl, mercapturate, and methylthio metabolites. It was found that garlic treatment had no discernible effect on oxidative metabolism but was associated with a slight increase in sulfate conjugation of drug. These findings suggest that garlic extract has limited potential as a chemopreventive agent.

Patient-specific dosimetry of indium-111- and yttrium-90-labeled monoclonal antibody CC49.

UNLABELLED: The objective of this work was to develop patient-specific dosimetry for patients with metastatic gastrointestinal tract cancers who received 111In-CC49 IgG for imaging before therapy with 90Y-CC49 IgG. METHODS: Whole-body imaging of 12 patients, who received 111-185 MBq (3-5 mCi) of 111In-CC49, commenced in < 2 hr postinfusion and was continued daily for 4-5 days. SPECT data were acquired at 24 and 72 hr to determine the range of 111In-CC49 activity concentrations in tumors and normal organs. Time-activity curves were generated from the image data and scaled from 111In-CC49 to 90Y-CC49 for dosimetric purposes. Absorbed-dose calculations for 90Y-CC49 included the mean and range in tumor and normal organs. Computed 90Y-CC49 activity concentrations were compared with measurements on 10 needle biopsies of normal liver and four tumor biopsies. RESULTS: In 9 of 10 normal liver samples, the range of computed 90Y-CC49 activity concentrations bracketed measured values. This was also the case for 3 of 4 tumor biopsies. Absorbed-dose calculations for 90Y-CC49 were based on patients' images and activities in tissue samples and, hence, were patient-specific. CONCLUSION: For the radiolabeled antibody preparations used in this study, quantitative imaging of 111In-CC49 provided the data required for 90Y-CC49 dosimetry. The range of activities in patients' SPECT images was determined for a meaningful comparison of measured and computed values. Knowledge of activity distributions in tumors and normal organs was essential for computing mean values and ranges of absorbed dose and provided a more complete description of the absorbed dose from 90Y-CC49 than was possible with planar methods.

Outpatient treatment with (131)I-anti-B1 antibody: radiation exposure to family members.

UNLABELLED: The Nuclear Regulatory Commission (NRC) regulations that govern release of patients administered radioactive material have been revised to include dose-based criteria in addition to the conventional activity-based criteria. A licensee may now release a patient if the total effective dose equivalent to another individual from exposure to the released patient is not likely to exceed 5 mSv (500 mrem). The result of this dose-based release limit is that now many patients given therapeutic amounts of radioactive material no longer require hospitalization. This article presents measured dose data for 26 family members exposed to 22 patients treated for non-Hodgkin's lymphoma with (131)I-anti-B1 antibody after their release according to the new NRC dose-based regulations. METHODS: The patients received administered activities ranging from 0.94 to 4.77 GBq (25--129 mCi). Family members were provided with radiation monitoring devices (film badges, thermoluminescent or optically stimulated luminescent dosimeters, or electronic digital dosimeters). Radiation safety personnel instructed the family members on the proper wearing and use of the devices. Instruction was also provided on actions recommended to maintain doses to potentially exposed individuals as low as is reasonably achievable. RESULTS: Family members wore the dosimeters for 2--17 d, with the range of measured dose values extending from 0.17 to 4.09 mSv (17--409 mrem). The average dose for infinite time based on dosimeter readings was 32% of the predicted doses projected to be received by the family members using the NRC method provided in regulatory guide 8.39. CONCLUSION: Therapy with (131)I-anti-B1 antibody can be conducted on an outpatient basis using the established recommended protocol. The patients can be released immediately with confidence that doses to other individuals will be below the 5-mSv (500 mrem) limit.

Radiolabeled iododeoxyuridine: safety evaluation.

UNLABELLED: The emphasis of radiolabeled iododeoxyuridine (*IUdR) research at our institution to date has been to assess its safety as a potential therapeutic agent. Toward this goal, we have performed preclinical and clinical studies, using various routes of administration, to detect adverse changes in normal tissues in both humans and animals. As IUdR is rapidly dehalogenated by the liver, the intravenous route is unlikely to be successful in therapeutic efforts. We have therefore focused our attention on more "protected" routes: intra-arterial and intravesicular administration. METHODS: Studies were performed in farm pigs after multiple administrations of [125I]IUdR into the aorta, carotid artery and bladder. IUdR and metabolites were measured in venous blood samples at appropriate time intervals after administration, after which histologic examination of tissues was performed. Studies in human have been performed after intra-arterial administration of [123I]IUdR in patients with liver metastases and intravesicular administration in patients with bladder carcinoma, initially using [123I]IUdR and currently using both [123I]IUdR and [125I]IUdR. Blood samples for pharmacokinetics and metabolite analysis and tissue for autoradiography (when feasible) have been obtained. RESULTS: To date, no evidence of adverse effects on normal tissue or alteration of hematologic or metabolic indices have been seen in pigs or humans. When instilled in the bladder, there is little leakage of IUdR in the circulation. CONCLUSION: When [125I]IUdR is used as a therapeutic agent, we anticipate little or no effect on normal tissues.

Reactivity of CO17-1A and B72.3 in benign and malignant pancreatic diseases.

The immunoreactivity of two monoclonal antibodies, CO17-1A (recognizing 17-1A antigen) and B72.3 (recognizing TAG-72), was examined in pancreatic tissues from individuals without pancreatic disease and from those with benign and malignant pancreatic disease. 17-1A antigen was found in all cells in the normal tissue, whereas TAG-72 was present in the duct cells in only one case. Both antigens were present in benign diseases; however, in some cells and in some conditions, TAG-72 was significantly less common (P less than .01 to .001) than 17-1A antigen. In pancreatic cancer, 17-1A antigen was present in 87% of cases and TAG-72 antigen was present in 92% of cases. The results indicate that B72.3 is more specific to pancreatic cancer than C017-1A.

Flow cytometric measurement of intracellular bilirubin in human peripheral blood mononuclear cells exposed to unconjugated bilirubin.

Human peripheral blood mononuclear cells were incubated at 37 degrees C with bilirubin in bovine albumin solution. Histological analysis of bilirubin-treated cells demonstrated a prominent brown pigment deposited in the cytoplasm. Homogenates of these cells in chloroform-methanol solution showed an identical absorption spectrum with pure bilirubin dissolved in the same solution. When bilirubin-treated cells were excited at 488 nm, a significant autofluorescence was detected by flow cytometry at 585 nm in a dose-dependent manner, which had a significant correlation with the amount of bilirubin chemically extracted from the cells (r = 0.963, n = 34, p less than 0.001). Intraassay and interassay variability of the autofluorescence by flow cytometric analysis was small (both less than 5%). When bilirubin-treated cells were stained with fluorescein-labeled anti-CD14 antibody, the CD14 positive cell population can be fractionated without interference of autofluorescence derived from intracellular bilirubin. These results suggest that flow cytometric analysis of bilirubin-treated cells can quantitate intracellular bilirubin, and that bilirubin does not interfere with analysis of surface antigens.

Diagnostic use of radiolabeled antibodies for cancer.

Antibodies against a variety of tumor-associated antigens have been studied, as well as a number of modifications to the antibodies themselves, including Fab' fragments and chimeric, humanized, and human antibodies. The appropriate use of radioimmunoconjugates in the evaluation of cancer patients has not yet been clearly defined. Only a few studies have assessed their use, primarily through the intravenous route, in initial disease staging. To date, immunolymphoscintigraphy has not proven promising in the staging of cancers. More emphasis has been given to the use of IV radioimmunoconjugates to detect residual and recurrent disease, with generally favorable results. In addition, radioimmunoguided surgery, using small, handheld probes to detect foci of antibody accumulation, appears to be a valuable tool. As better production techniques become available and large clinical trials provide more clearly defined indications for radioimmunoconjugate use, these agents should enter the arena for routine diagnostic use.

The effect of selenium on cell proliferation in liver and colon.

Epidemiologic and experimental evidence support a chemoprotective role for selenium (Se) in malignancy. Many mechanisms have been proposed to explain this phenomenon. In this study, the effect of Se intake on proliferation of hepatocytes and normal colonic epithelial cells in rats was determined using autoradiographic analysis of thymidine incorporation into DNA. Hepatocyte proliferation was measured 24 h after partial hepatectomy. Selenium-dosed animals demonstrated a significant reduction in hepatocyte labeling compared to the control group (6.1±2.6 vs 29.2±15.6,p=0.003). However, Se dosing did not affect the thymidine-labeling indices or distribution of labeling in colonic epithelium. Selenium may inhibit cell proliferation when it is the result of an unusually intense stimulus. This finding could explain in part the inhibitory effect of Se in some experimental cancer models.

In vitro regulation of human lymphocyte proliferation by selenium.

A chemoprotective role for dietary selenium in malignancy has been well documented in numerous epidemiological and experimental studies. The precise mechanisms of this relationship are not understood, but may be related to observations that selenium can inhibit the proliferation of various normal and neoplastic cells, both in vivo and in vitro. In this study, we present evidence that selenium at physiologic concentrations can effectively inhibit the overall proliferation of human lymphocyte populations in response to various immune stimuli in vitro, including mixed lymphocyte response and response to soluble antigen (tetanus toxoid). This inhibition was reversible, indicating that selenium was not toxic to the lymphocytes at these concentrations. Preliminary data from our laboratory indicate that the antiproliferative effects of selenium may be specific for certain lymphocyte subsets. Similar modulation of immune responses in vivo could enhance various humoral and cellular immune mechanisms. Together with published evidence that selenium can inhibit tumor cell proliferation, these data may help to explain the decreased incidence of cancer associated with elevated selenium intake.