seocalcitol and Pancreatic-Neoplasms

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10-15 microg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Calcitriol; Carcinoma; Disease Progression; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis; Treatment Outcome

Vitamin D insufficiency and deficiency are common among patients with pancreatic carcinoma, but epidemiological studies have shown inconsistent results for vitamin D intake/circulation level and pancreatic cancer risk. The study aims were to investigate the effects of vitamin D on patient survival, and the proliferation or survival of pancreatic cancer cell lines.. The present study examined the local expression of vitamin D receptor (VDR) in pancreatic normal and tumour tissues from a cohort of 61 patients, and analysed the potential correlation between VDR and pathological characteristics, including disease prognosis. Among 61 pairs of normal and tumour specimens, VDR was detected in all normal tissues, and was abundantly expressed in 62.5% (15/24) of tumour tissues with high differentiation, but had a significantly lower or undetectable expression level in 75.7% (28/37) of tissues with moderate or low differentiation (P = 0.004). Moreover, high VDR expression was detected in 63.6% (14/22) of small tumours (≤25 mm) and in only 25.6% (10/39) of large tumours (>25 mm) (P = 0.06). Kaplan-Meier analysis showed that a low level of VDR expression in tumour tissues was associated with a poor prognosis (P = 0.037).. VDR expression could be a potential prognostic factor for patients with pancreatic adenocarcinoma, and its effects should be examined in a prospective study. Vitamin D analogues may provide a therapeutic choice for patients with high VDR expression in tumours but a low vitamin D level in the circulation.

Topics: Aged; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Calcitriol; Carcinoma, Pancreatic Ductal; Cell Differentiation; Cell Line, Tumor; Cohort Studies; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pancreatic Neoplasms; Prognosis; Receptors, Calcitriol

Previous research has shown that the retinoid 9-cis retinoic acid (RA) promotes apoptosis in pancreatic cancer cells. The vitamin D analog EB1089 does not. Furthermore, cotreatment of cells with 9-cis RA and EB1089 abrogates apoptosis. To explain this, we studied the regulation of proteins involved in apoptotic signaling pathways in pancreatic cancer cells.. The pancreatic adenocarcinoma cell line T3M4 was used. Cell proliferation was measured using the SRB protein dye assay. Induction of apoptosis was evaluated using an ELISA assay. Caspase activation was detected using a colorimetric assay based on cleavage of a caspase-associated substrate. Regulation of protein levels and posttranslational events were detected using immunoblotting.. We confirm that EB1089 diminishes apoptosis induced by 9-cis RA in T3M4 cells. We extend the study to show that EB1089 abrogates increases, induced by 9-cis RA, in caspase activation, p27Kip1 protein levels, Bim and Bax protein levels and in Bax/Bcl2 ratio. In addition, the CDKI p21Waf1 and CAII, a differentiation marker for pancreatic cancer cells are also differentially regulated.. These results suggest that the inhibitory effects of EB1089 on 9-cis RA-induced apoptosis lie upstream of caspase activation and could be associated with reduction of p27Kip1 protein levels.

Topics: Adenocarcinoma; Alitretinoin; Antineoplastic Agents; Apoptosis; Calcitriol; Caspases; Cell Division; Cell Line, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Enzyme-Linked Immunosorbent Assay; Humans; Pancreatic Neoplasms; Tretinoin

The vitamin D-receptor (VDR) has been detected in both normal and malignant cells of different tissues. Treatment with vitamin D(3) has been suggested as a possible therapy in malignant diseases such as pancreatic cancer. Synthetic analogues of vitamin D(3) have a less hypercalcemic effect than native vitamin D(3). The aim was to study the expression of the VDR in human pancreatic cancers and to study the in vitro effect of an analogue to vitamin D(3) on cell lines established from these cancers.. The pancreatic cancer cell lines were established from primary cultures with only cancer cells. A probe specific for the human VDR was used. After reverse-transcriptase PCR and Northern blotting, the expression of the VDR in normal pancreas and in pancreatic cancers was compared. The cell lines were incubated with EB 1089, a synthetic analogue vitamin of D(3), in dose-response studies. The cell number was measured by the XTT colorimetric method.. The VDR was expressed in all cancers and in six of the cell lines the expression was increased more than 3-fold compared to normal pancreas. All cell lines developed from human pancreatic cancers responded with a decreased cell number to the vitamin D(3) analogue at concentrations of 10(-5) M or higher.. The VDR was expressed in all pancreatic cancers studied. Cell lines derived from these cancers responded with a decrease in cell number to high concentrations of a vitamin D(3) analogue. These results, and the doses to use, have to be confirmed with in vivo studies.

Topics: Antineoplastic Agents; Calcitriol; Cell Count; Dose-Response Relationship, Drug; Humans; Pancreatic Neoplasms; Receptors, Calcitriol; RNA, Messenger; Tumor Cells, Cultured

Retinoids and vitamin D are known to exert important anti-tumour effects in a variety of cell types. In this study the effects of 9-cis-retinoic acid (9cRA) the vitamin D analogues EB1089 and CB1093 on three pancreatic adenocarcinoma cell lines were investigated. All compounds caused inhibition of in vitro growth but the vitamin D analogues were generally the more potent growth inhibitors. They were also more effective on their own than in combination with 9cRA. Growth arrest correlated with an increased proportion of cells in the G0/G1 phase. Apoptosis was induced in the three cell lines by 9cRA, whereas neither EB1089 nor CB1093 had this effect. Furthermore, addition of EB1089 or CB1093 together with 9cRA resulted in significantly reduced apoptosis. Our results show that retinoic acids as well as vitamin D analogues have inhibitory effects on pancreatic tumour cells but different and antagonistic mechanisms seem to be employed.

Topics: Alitretinoin; Antineoplastic Agents; Apoptosis; Calcitriol; Cell Division; Drug Screening Assays, Antitumor; Humans; Pancreatic Neoplasms; Tretinoin; Tumor Cells, Cultured; Vitamin D

The GER human pancreatic carcinoma cell line possesses receptors for 1,25-dihydroxyvitamin D3. We report that the vitamin D analogue EB 1089 inhibits the growth of these cells in vitro and when grown as tumour xenografts in immunodeficient mice. Tumour-bearing mice were given EB 1089 at a dose of 5 microg kg(-1) body weight i.p. thrice weekly for 4-6 weeks. Tumour growth was significantly inhibited in treated animals compared with controls in the absence of hypercalcaemia. These findings may have therapeutic implications in pancreatic cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Calcitriol; Cell Division; Dose-Response Relationship, Drug; Female; Humans; Mice; Mice, Nude; Neoplasm Transplantation; Pancreatic Neoplasms; Receptors, Calcitriol; Transplantation, Heterologous; Tumor Cells, Cultured

Retinoids and vitamin D are important factors that regulate cellular growth and differentiation. An additive growth-inhibitory effect of retinoids and vitamin D analogues has been demonstrated for human myeloma, leukaemic and breast cancer cells. We set out to study the effects of the vitamin D analogue EB1089 and the retinoids all-trans- and 9-cis-retinoic acid on the human pancreatic adenocarcinoma cell lines Capan 1 and Capan 2 and the undifferentiated pancreatic carcinoma cell line Hs766T. The cell lines investigated expressed vitamin D receptor, retinoic acid receptor (RAR)-alpha and gamma as determined by polymerase chain reaction after reverse transcription. RAR-beta was expressed only in Hs766T cells. Addition of all-trans-retinoic acid increased the amount of RAR-alpha mRNA in the three cell lines and induced RAR-beta mRNA in Capan 1 and Capan 2 cells. All-trans-retinoic acid at a concentration of 10 nM inhibited the growth of Capan 1 and Capan 2 cells by 40% relative to controls. 9-cis-Retinoic acid was less effective. Neither all-trans-retinoic acid nor 9-cis-retinoic acid affected the growth of Hs766T cells. EB1089, if added alone to the cells, did not significantly inhibit growth. However, the combination of 1 nM EB1089 with 10 nM all-trans-retinoic acid exerted a growth-inhibitory effect of 90% in Capan 1 cells and of 70% in Capan 2 cells. Our data suggest that vitamin D analogues together with retinoids inhibit the growth of human pancreatic cancer cells. However, in vivo studies are necessary to examine the potential use of retinoids and vitamin D analogues on pancreatic cancer.

Topics: Animals; Antineoplastic Agents; Base Sequence; beta 2-Microglobulin; Calcitriol; Cell Division; Cell Line; DNA Primers; Kidney; Molecular Sequence Data; Pancreatic Neoplasms; Polymerase Chain Reaction; Rats; Receptors, Calcitriol; Receptors, Retinoic Acid; Retinoic Acid Receptor alpha; Transcription, Genetic; Tretinoin; Tumor Cells, Cultured