isotretinoin and Pancreatic-Neoplasms

The antitumor activity and toxicity of a multi-step treatment were evaluated in patients with locally advanced, inoperable, or incompletely resected pancreatic (Pa) and biliary tree (Bt) adenocarcinomas (ADKs).. Fifty-four patients, 63% with Pa and 37% with Bt ADK, received 3 courses of cisplatin-gemcitabine induction chemotherapy. Progression-free (PF) patients were given consolidation radiotherapy with concurrent capecitabine. PF patients had, as maintenance immunotherapy (MI), interleukin 2 (1.8x10 IU) and 13-cis-retinoic acid (0.5 mg/kg) [DOSAGE ERROR CORRECTED].. Thirty-eight patients, 27 with Pa and 11 with Bt ADKs, PF after cisplatin/gemcitabine, were treated with consolidation radiotherapy with concurrent capecitabine. Fourteen PF patients, 7 with Pa and 7 with Bt ADK, received MI. Median PF and overall survivals (OS) for all 54 patients were 6.8 and 12.1 months, respectively. Patients treated with MI had a median PF survival of 16.2 months, whereas median OS had not been reached yet, after a median follow-up of 27.5 months.. Grades 3 and 4 hematological and gastrointestinal in 30% and 37% of patients, respectively; grades 1 and 2 autoimmune reactions in 28% of patients.. These results support the efficacy and safety of a multi-step sequential treatment in patients with locally advanced, inoperable or incompletely resected Pa and Bt ADKs.

Topics: Adenocarcinoma; Adult; Aged; Algorithms; Antineoplastic Agents; Biliary Tract Neoplasms; Capecitabine; Cisplatin; Combined Modality Therapy; Deoxycytidine; Disease-Free Survival; Female; Fluorouracil; Gemcitabine; Humans; Immunotherapy; Interleukin-2; Isotretinoin; Kaplan-Meier Estimate; Male; Middle Aged; Pancreatic Neoplasms

Adenocarcinoma of the pancreas is a cancer with extremely poor prognosis and limited therapeutic options. Retinoids are derivatives of vitamin A involved in the control of many biological functions, including cell growth and differentiation and the induction of apoptosis. On the basis of pre-clinical evidence and some clinical data, we conducted a phase II study of 13-cis-retinoic acid (13-cis-RA) in combination with gemcitabine in patients with unresectable pancreatic carcinoma.. Patients with histologically confirmed unresectable pancreatic carcinoma were treated with gemcitabine 1000 mg/m2 on days 8, 15, 22 plus 13-cis-RA 1 mg/kg on days 1-14 for six cycles. The end points included the objective response rate and median survival.. Thirty patients were recruited, 15 men and 15 women; 20 patients were evaluable. The median age was 65 years (range 44-79 years) and the median Karnofsky performance status was 80% (range 60-100%). The median follow-up was 21 months. One patient achieved a partial remission, seven patients had stable disease and 12 patients developed progressive disease. Toxicity was mainly haematological, with eight cases of grade 3 and four cases of grade 4 neutropenia, thrombocytopenia and anaemia. The median survival was 7.8 months (range 2.6-21.6 months).. The combination of gemcitabine and 13-cis-RA was well tolerated, but we did not see improvement in the response rate. Further studies with other retinoids may be beneficial to patients with unresectable pancreatic cancer.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Deoxycytidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gemcitabine; Humans; Isotretinoin; Liver Neoplasms; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Palliative Care; Pancreatic Neoplasms; Pilot Projects; Prognosis; Ribonucleotide Reductases; Survival Rate; Treatment Outcome

Advanced unresectable pancreatic adenocarcinoma has a dismal prognosis. The authors previously have shown that retinoic acid (RA) and interferon-alpha (IFN-alpha) inhibit growth and induce differentiation in human pancreatic carcinoma cells in vitro and in vivo. The purpose of this trial was to examine the feasibility and tolerability of a combination therapy of 13-cis RA and IFN-alpha in patients with advanced unresectable pancreatic carcinoma.. Twenty-two patients (median age, 62 years) with histologically confirmed, unresectable pancreatic adenocarcinoma classified as International Union Against Cancer Stage III (5 patients) or IV (17 patients) were included. Patients received 1 mg/kg body weight 13-cis RA orally and 6 million IU IFN-alpha subcutaneously daily. Restaging by ultrasound, computed tomography scan, and chest X-ray was performed every 2 months.. No complete remission and 1 partial remission (PR) (4.5%) were observed. Fourteen patients (63.6%) demonstrated stable disease with a median duration of 5.0 months (range, 2.3-17.7+ months). Toxicity mainly was related to IFN-alpha and predominantly was hematologic (no toxicity was World Health Organization [WHO] Grade 4 and 13.6% were WHO Grade 3). Nonhematologic toxicities did not exceed Grade 2 (skin and oral mucosa) and mainly were related to 13-cis RA. The median survival of the patients with Stage III disease was 8.7 months (range, 6.8-23.9+ months) and was 7.4 months for patients with Stage IV disease (range, 0.9-19.2+ months), resulting in a median overall survival of 7.7 months (range, 0.9-23.9+ months).. Combination therapy with 13-cis RA and IFN-alpha is feasible and well tolerated in patients with advanced pancreatic carcinoma. Based on the median survival rates observed in this study this combination should be investigated further in Phase III trials.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Interferon-alpha; Isotretinoin; Male; Middle Aged; Neoplasm Staging; Pancreatic Neoplasms; Pilot Projects; Survival Rate

The combination of interferons (IFNs) and retinoids in antineoplastic therapy is based upon preclinical, in vitro, and in vivo observations. Retinoid-IFN combinations have shown significant antitumor activity against advanced cutaneous and cervical squamous cell carcinoma (SCC), and the toxic effects do not appear to overlap. Based on in vitro evidence of synergy and observed clinical activity, we conducted a pilot phase II trial of 13-cis-retinoic acid (1 mg/kg/day) and IFN alpha (6 million units/day) in patients with advanced pancreatic adenocarcinoma. No objective responses occurred among six evaluable patients. The toxicities were mild and reversible, and grade 3 fatigue occurred in only one patient. No objective antitumor activity was noted against pancreatic adenocarcinomas at the dose and schedule utilized. Further exploration of this this purely biological approach is not warranted for pancreatic adenocarcinomas.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Combined Modality Therapy; Female; Humans; Interferon alpha-2; Interferon-alpha; Isotretinoin; Male; Middle Aged; Pancreatic Neoplasms; Pilot Projects; Recombinant Proteins

Human pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer type with a very high mortality rate. Inflammatory cytokine such as tumor necrosis factor- alpha (TNF-α) plays a pivotal role in the progression of PDAC. Recently, suppression of cell invasion by preventive agents has received considerable attention in the prevention of metastatic tumors. Several clinical studies suggested that natural forms or analogues of fat-soluble vitamins such as vitamin A and vitamin D can work as anti-cancer agents to inhibit the development of cancer. In this study, our results demonstrated that co-treatment of 13-cis retinoic acid (13-cis RA) and 1,25-dihydroxyvitamin D3 (1,25-VD3) significantly inhibited TNF-α mediated cell invasion in PDAC in vitro. Cotreatment of 13-cis RA and 1,25-VD3 also inhibited TNF-α mediated expression of matrix metalloproteinase-9 (MMP-9) protein through blocking c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB) signaling pathways. Our results demonstrated that treatment of TNF-α lead to a decreased expression of tissue inhibitor of metalloproteinase- 3 (TIMP-3) protein and an induction of MMP-9 protein and cell invasion through an upregulation of microRNA-221 (miR-221) in human PDAC cells. Moreover, treatment of SP600125 (a specific inhibitor of JNK pathway) or cotreatment of 13-cis RA and 1,25-VD3 significantly induced a decreased expression of miR-221 and an increased expression of TIMP-3 protein. These results suggest that 13-cis RA and 1,25-VD3 significantly suppress TNF-α mediated cell invasion and therefore potentially act as preventive agents against PDAC.

Topics: Adenocarcinoma; Anthracenes; Calcitriol; Cell Line, Tumor; Cell Movement; Cell Survival; Humans; Isotretinoin; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Matrix Metalloproteinase 9; MicroRNAs; Neoplasm Invasiveness; NF-kappa B; Pancreatic Neoplasms; Phosphorylation; Tissue Inhibitor of Metalloproteinase-3; Transfection; Tumor Necrosis Factor-alpha; Up-Regulation

Neuroblastoma is the leading cause of cancer death in children aged 1 to 4 years. Particularly, five-year overall survival for high-risk neuroblastoma is below 50% with no curative options when refractory or relapsed. Most of current therapies target cell division and proliferation, thereby inducing DNA damage and programmed cell death. However, aggressive tumours often present alterations of these processes and are resistant to therapy. Therefore, exploring alternative pathways to induce tumour cell death will provide new therapeutic opportunities for these patients. In this study we aimed at testing the therapeutic potential of ABTL0812, a novel anticancer drug that induces cytotoxic autophagy to eliminate cancer cells, which is currently in phase II clinical trials of adult tumours. Here, we show that ABTL0812 impaired the viability of clinical representative neuroblastoma cell lines regardless of genetic alterations associated to bad prognosis and resistance to therapy. Oral administration of ABTL0812 to mice bearing neuroblastoma xenografts impaired tumour growth. Furthermore, our findings revealed that, in neuroblastoma, ABTL0812 induced cancer cell death via induction of endoplasmic reticulum stress, activation of the unfolded protein response, autophagy and apoptosis. Remarkably, ABTL0812 potentiated the antitumour activity of chemotherapies and differentiating agents such as irinotecan and 13-cis-retinoic acid. In conclusion, ABTL0812 distinctive mechanism of action makes it standout to be used alone or in combination in high-risk neuroblastoma patients.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Cell Line, Tumor; Cell Proliferation; DNA Damage; Drug Development; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Female; Humans; Inhibitory Concentration 50; Isotretinoin; Linoleic Acids; Mice; Neoplasm Transplantation; Neuroblastoma; Pancreatic Neoplasms; Unfolded Protein Response

Patients with pancreatic ductal adenocarcinoma are deficient in vitamin A, resulting in activation of pancreatic stellate cells (PSCs). We investigated whether restoration of retinol to PSCs restores their quiescence and affects adjacent cancer cells.. PSCs and cancer cell lines (AsPc1 and Capan1) were exposed to doses and isoforms of retinoic acid (RA) in 2-dimensional and 3-dimensional culture conditions (physiomimetic organotypic culture). The effects of all-trans retinoic acid (ATRA) were studied in LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre mice, a model of human pancreatic ductal adenocarcinoma.. After incubation with ATRA, PSCs were quiescent and had altered expression of genes that regulate proliferation, morphology, and motility; genes that encode cytoskeletal proteins and cytokines; and genes that control other functions, irrespective of culture conditions or dosage. In the organotypic model, and in mice, ATRA induced quiescence of PSCs and thereby reduced cancer cell proliferation and translocation of β-catenin to the nucleus, increased cancer cell apoptosis, and altered tumor morphology. ATRA reduced the motility of PSCs, so these cells created a "wall" at the junction between the tumor and the matrix that prevented cancer cell invasion. Restoring secreted frizzled-related protein 4 (sFRP4) secretion to quiescent PSCs reduced Wnt-β-catenin signaling in cancer cells and their invasive ability. Human primary and metastatic pancreatic tumor tissues stained strongly for cancer cell nuclear β-catenin but had low levels of sFRP4 (in cancer cells and PSCs).. RA induces quiescence and reduces motility of PSCs, leading to reduced proliferation and increased apoptosis of surrounding pancreatic cancer cells. RA isoforms might be developed as therapeutic reagents for pancreatic cancer.

Topics: Alitretinoin; Animals; Antineoplastic Agents; Apoptosis; beta Catenin; Carcinoma, Pancreatic Ductal; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cellular Senescence; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Isotretinoin; Mice; Mice, Mutant Strains; Pancreatic Neoplasms; Pancreatic Stellate Cells; Paracrine Communication; Proto-Oncogene Proteins; RNA Interference; Signal Transduction; Time Factors; Transcription, Genetic; Tretinoin; Wnt Proteins

Analogues of vitamin A have been shown to influence growth of malignant tissue, such as pancreatic cancer.. To study the expression of retinoic acid receptors (RAR) in pancreatic cancer cells and the effect of three different retinoids on the cell number in vitro were studied.. Cell lines were established from 13 patients who underwent surgery for pancreatic adenocarcinoma. The expression of the retinoic acid receptors (RAR) and retinoic X receptor (RXR) subtypes (alpha, beta, and gamma) was studied with western blotting and specific antibodies. The effect of incubation with all-trans-retinoic acid (atRA; tretinoin), 9-cis-retinoic acid (9-cis-RA), and 13-cis-retinoic acid (13-cis-RA; isotretinoin) on the cell number was examined with use of a Roche XTT cell proliferation kit.. The RXR alpha receptor was expressed in all cell lines. RAR alpha,beta and RXR beta were expressed in most of them. RXR gamma was expressed in about half of the cell lines and RAR gamma in only one. Incubation of the cells with retinoids showed a decreased cell number at concentrations of 10(4) M, except for 9-cis-RA, to which only about half of the cell lines responded.. Two or more of the RAR subtypes were expressed in each pancreatic cell line. There was no uniform pattern of receptor expression; however, the cell lines responded with decreased cell number to high concentrations of atRA and 13-cis-RA but not to 9-cis-RA.

Topics: Adenocarcinoma; Alitretinoin; Antineoplastic Agents; Blotting, Western; Cell Division; Dose-Response Relationship, Drug; Humans; In Vitro Techniques; Isotretinoin; Pancreatic Neoplasms; Receptors, Retinoic Acid; Retinoid X Receptors; Transcription Factors; Tretinoin; Tumor Cells, Cultured

We have investigated the effects of retinoic acid (RA) on matrix metalloprotease-1 (MMP-1) gene expression in the human pancreatic tumour cell line Dan-G. 13-cis RA results in a time- and dose-dependent increase of MMP-1 protein concentration. These stimulatory effects were paralleled by a time- and dose-dependent increase of MMP-1 mRNA steady-state concentrations. Nuclear run-on analysis revealed that the increase of MMP-1 mRNA was partially due to an increase of MMP-1 gene transcription. In addition, 13-cis RA treatment results in an increase of MMP-1 mRNA stability. These data demonstrate that RA stimulates MMP-1 gene expression in human pancreatic carcinoma cells by transcriptional and post-transcriptional mechanisms.

Topics: Blotting, Northern; Blotting, Western; Collagenases; Dose-Response Relationship, Drug; Gene Expression Regulation, Neoplastic; Humans; Isotretinoin; Matrix Metalloproteinase 1; Pancreatic Neoplasms; RNA, Messenger; Transcription, Genetic; Tumor Cells, Cultured

Effective chemotherapy for pancreatic cancer is urgently needed. The anti-proliferative activity of a new retinoid, mofarotene (RO40-8757), was compared with that of other retinoids, such as all trans-retinoic acid, 13-cis retinoic acid and 9-cis retinoic acid, on 9 pancreatic cancer cell lines in relation to the effects on various cell cycle-regulating factors. After treatment with each retinoid, anti-proliferative effect was determined by the MTT method and expression of cell cycle-regulating factors, such as cyclins (D1, E and A), cyclin-dependent kinases (2 and 4), cyclin-dependent kinase inhibitors (p21 and p27) and retinoblastoma protein, was analyzed by Western blotting. Mofarotene showed half-maximal inhibition of cell proliferation at concentrations between 0.14 x 10(-6) and 3.8 x 10(-6) mol/l with little cytotoxicity. In contrast, the other retinoids did not inhibit the growth of all cell lines by over 50% compared to controls. A marked increase in the fraction of cells in G1 phase of the cell cycle was observed after mofarotene treatment; this was associated with marked up-regulation of p21/p27 and a shift of retinoblastoma protein into the hypophosphorylated form. In conclusion, mofarotene inhibits the growth of pancreatic cancer cells by inducing G1-phase cell cycle-inhibitory factors (p21, p27 and hypophosphorylated form of Rb protein) and is considered to be a useful agent for pancreatic cancer treatment.

Topics: Alitretinoin; Antineoplastic Agents; Blotting, Western; CDC2-CDC28 Kinases; Cell Cycle; Cell Cycle Proteins; Cell Division; Cyclin-Dependent Kinase 2; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor p21; Cyclin-Dependent Kinase Inhibitor p27; Cyclin-Dependent Kinases; Cyclins; Dose-Response Relationship, Drug; Humans; Isotretinoin; Microtubule-Associated Proteins; Morpholines; Pancreatic Neoplasms; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Retinoblastoma Protein; Retinoids; Time Factors; Tretinoin; Tumor Cells, Cultured; Tumor Suppressor Proteins; Up-Regulation

Syrian hamsters were treated with either a low (10 mg/kg body weight) or high (40 mg/kg body weight) single dose of bis(2-oxopropyl)nitrosamine (BOP) and beginning 1 week later fed either low (0.2 mmol/kg diet) or high (0.4-1.0 mmol/kg diet) levels of one of four retinoids [13 cis retinoic acid (13-cis-RA), N-ethylretinamide (ERA), N-(2-hydroxyethyl)retinamide (OHERA) or N-(phenyl)retinamide (PRA)] for periods of 40 or 50 weeks. The high retinoid levels (0.4-1.0 mmol/kg diet) fed following the highest BOP treatment enhanced pancreatic carcinoma yields (average number/effective animal) in males fed all four retinoids, and in females fed ERA and 13-cis-RA. Enhanced adenoma yields were also seen in all groups when high retinoid levels were fed following 40 mg BOP/kg body weight. However, these retinoid levels caused an increased adenoma yield in male hamsters only and did not modify carcinoma yields when fed following 10 mg BOP/kg body weight. Similarly, tumor yields at extra-pancreatic sites were elevated in retinoid-fed hamsters of both sexes after 40 mg BOP/kg body weight and in males fed ERA and 13-cis-RA after 10 mg BOP/kg body weight when retinoids were given at the high levels (0.4-1.0 mmol/kg diet). Increased incidences of bile duct and liver tumors in particular were found in hamsters given 40 mg BOP/kg body weight. Consumption of retinoid levels of 0.4 mmol/kg diet and above was also associated with a high incidence of liver cell necrosis, ovarian cysts and ovarian hemorrhage. Retinoids (ERA, OHERA, and PRA) fed at the low level (0.2 mmol/kg diet) following the low BOP dose did not enhance carcinogenesis in the pancreas or at other sites and did not cause alterations in morphologic observations.

Topics: Animals; Body Weight; Cricetinae; Dose-Response Relationship, Drug; Female; Isomerism; Isotretinoin; Male; Mesocricetus; Neoplasms; Nitrosamines; Pancreatic Neoplasms; Sex Factors; Tretinoin