https://itb.biologie.hu-berlin.de/~kempter/Hippocampus_Journal_Club/Articles/lisman05.pdf

The Hippocampal-VTA Loop: Controlling the Entry of Information into Long-Term Memory

Abnormal dendritic cell differentiation and accumulation of immature myeloid suppressor cells (ImC) is one of the major mechanisms of tumor escape. We tested the possibility of pharmacologic regulation of myeloid cell differentiation using all-trans-retinoic acid (ATRA). Eighteen patients with metastatic renal cell carcinoma were treated with ATRA followed by s.c. interleukin 2 (IL-2). Eight healthy individuals comprised a control group. As expected, the cancer patients had substantially elevated levels of ImC. We observed that ATRA dramatically reduced the number of ImC. This effect was observed only in patients with high plasma concentration of ATRA (>150 ng/mL), but not in patients with lower ATRA concentrations (<135 ng/mL). Effects of ATRA on the proportions of different dendritic cell populations were minor. However, ATRA significantly improved myeloid/lymphoid dendritic cell ratio and the ability of patients' mononuclear cells to stimulate allogeneic T cells. This effect was associated with significant improvement of tetanus-toxoid-specific T-cell response. During the IL-2 treatment, the ATRA effect was completely eliminated. To assess the role of IL-2, specimens from 15 patients with metastatic renal cell carcinoma who had been treated with i.v. IL-2 alone were analyzed. In this group also, IL-2 significantly reduced the number and function of dendritic cells as well as T-cell function. These data indicate that ATRA at effective concentrations eliminated ImC, improved myeloid/lymphoid dendritic cell ratio, dendritic cell function, and antigen-specific T-cell response. ATRA treatment did not result in significant toxicity and it could be tested in therapeutic combination with cancer vaccines.

https://cancerres.aacrjournals.org/content/canres/66/18/9299.full.pdf

All-trans-Retinoic Acid Improves Differentiation of Myeloid Cells and Immune Response in Cancer Patients

The mechanisms of retinoid activity in tumors remain largely unknown. Here we establish that retinoids cause extensive apoptosis of medulloblastoma cells. In a xenograft model, retinoids largely abrogated tumor growth. Using receptor-specific retinoid agonists, we defined a subset of mRNAs that were induced by all active retinoids in retinoid-sensitive cell lines. We also identified bone morphogenetic protein-2 (BMP-2) as a candidate mediator of retinoid activity. BMP-2 protein induced medulloblastoma cell apoptosis, whereas the BMP-2 antagonist noggin blocked both retinoid and BMP-2-induced apoptosis. BMP-2 also induced p38 mitogen-activated protein kinase (MAPK), which is necessary for BMP-2- and retinoid-induced apoptosis. Retinoid-resistant medulloblastoma cells underwent apoptosis when treated with BMP-2 or when cultured with retinoid-sensitive medulloblastoma cells. Retinoid-induced expression of BMP-2 is thus necessary and sufficient for apoptosis of retinoid-responsive cells, and expression of BMP-2 by retinoid-sensitive cells is sufficient to induce apoptosis in surrounding retinoid-resistant cells.

BMP-2 mediates retinoid-induced apoptosis in medulloblastoma cells through a paracrine effect.

Purpose SPI-077 and SPI-077 B103 are formulations of cisplatin encapsulated in pegylated STEALTH liposomes that accumulate in tumors. However, the extent to which active platinum (Pt) is released from the liposome is unknown. Thus, we evaluated the disposition of encapsulated and released Pt in plasma and tumors after administration of STEALTH liposomal and nonliposomal cisplatin. Methods Cisplatin (10 mg/kg), SPI-077 (10 mg/kg), and SPI-077 B103 (5 mg/kg) were administered i.v. to mice bearing B16 murine melanoma tumors. Microdialysis probes were placed into the right and left sides of each tumor, and serial samples were collected from tumor extracellular fluid (ECF) after administration of each agent. After each microdialysis procedure, tumor samples were obtained at each probe site to measure total Pt and Pt-DNA adducts. In a separate study, serial plasma samples (three mice per time point) were obtained. Unbound Pt in tumor ECF and plasma, and total Pt in tumor homogenates were measured by flameless atomic absorption spectrophotometry. Area under the tumor ECF (AUC(ECF)) concentration versus time curves of unbound Pt were calculated. Intrastrand GG (Pt-GG) and AG (Pt-AG) Pt-DNA adducts were measured via (32)P-postlabeling. Results Mean+/-SD peak concentrations of total Pt in tumor homogenates after administration of cisplatin, SPI-077, and SPI-077 B-103 were 3.2+/-1.9, 11.9+/-3.0, and 3.5+/-0.3 microg/g, respectively. After cisplatin, mean+/-SD AUC(ECF) of unbound Pt was 0.72+/-0.46 microg/ml.h. There was no detectable unbound Pt in tumor ECF after SPI-077 or SPI-077 B-103 treatment. Mean+/-SD peak concentration of Pt-GG DNA adducts after administration of cisplatin, SPI-077, and SPI-077 B-103 were 13.1+/-3.3, 3.5+/-1.3, and 2.1+/-0.3 fmol Pt/microg DNA, respectively. Conclusion This study suggests that more SPI-077 and SPI-077 B103 distribute into tumors, but release less Pt into tumor ECF, and form fewer Pt-DNA adducts than does cisplatin.

Systemic and tumor disposition of platinum after administration of cisplatin or STEALTH liposomal-cisplatin formulations (SPI-077 and SPI-077 B103) in a preclinical tumor model of melanoma.

Retinoic acid (RA) protects mice from diet-induced obesity. The activity is mediated in part through activation of the nuclear receptors RA receptors (RARs) and peroxisome proliferator–activated receptor β/δ and their associated binding proteins cellular RA binding protein type II (CRABP-II) and fatty acid binding protein type 5 in adipocytes and skeletal muscle, leading to enhanced lipid oxidation and energy dissipation. It was also reported that RA inhibits differentiation of cultured preadipocytes. However, whether the hormone suppresses adipogenesis in vivo and how the activity is propagated remained unknown. In this study, we show that RA inhibits adipocyte differentiation by activating the CRABP-II/RARγ path in preadipose cells, thereby upregulating the expression of the adipogenesis inhibitors Pref-1, Sox9, and Kruppel-like factor 2 (KLF2). In turn, KLF2 induces the expression of CRABP-II and RARγ, further potentiating inhibition of adipocyte differentiation by RA. The data also indicate that RA suppresses adipogenesis in vivo and that the activity significantly contributes to the ability of the hormone to counteract diet-induced obesity.

https://diabetes.diabetesjournals.org/content/diabetes/61/5/1112.full.pdf

Retinoic Acid Upregulates Preadipocyte Genes to Block Adipogenesis and Suppress Diet-Induced Obesity

A phase I trial of all-trans-retinoic acid (ATRA) was conducted to establish the maximum tolerable dose (MTD) of ATRA given once daily to patients with solid tumors. Cancer patients for whom no standard therapy was available were treated with ATRA once daily. Doses were escalated in cohorts of at least three patients. The pharmacokinetics of ATRA were assessed on day 1 for all patients and weekly for 31 patients who received doses of ≥110 mg/m2 per day. Patients were followed for toxicity and response. Correlations of toxicity frequency and grade with pharmacokinetic parameters were sought. In addition, correlation of changes in ATRA pharmacokinetics with the concentration of ATRA metabolites in plasma were sought. A total of 49 patients received ATRA at doses ranging from 45 to 309 mg/m2 per day. Hypertriglyceridemia was dose-limiting at 269 mg/m2 per day. Other frequent toxicities included mucocutaneous dryness and headache. With chronic dosing, plasma ATRA concentrations fell in 59% of patients. Stable, low, or variable [ATRA] were seen in 16%, 6%, and 16% of patients respectively. Age, gender, smoking, or concurrent medication did not correlate with the pharmacokinetic pattern. Severe toxicities tended to occur with initial peak [ATRA] of ≥0.5 μg/ml (1.7 μM), and the toxicity frequency did not change if [ATRA] decreased with continued dosing. No consistent change in 4-oxo-ATRA or retinoid glucuronide concentrations was observed with decreases in plasma [ATRA]. The recommended once-daily ATRA dose is 215 mg/m2, although significant interpatient variability is observed in toxicity and plasma retinoid concentrations. Although not statistically significant, more frequent and severe toxicity tended to occur in patients with higher plasma peak ATRA concentrations. Other factors, such as responses at target tissues, may be at least as important as the plasma ATRA concentration in predicting toxicity and/or response.

Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics

Purpose: The efficacy of 13-cis-retinoic acid (13-CRA) given as a single agent or in combination with tamoxifen (TAM) was determined in athymic nude mice bearing advanced s.c. MCF-7 human breast cancers. Methods: 13-CRA alone was given by gavage at doses ranging from 26.4 to 200 mg/kg. TAM alone was given by gavage at doses of 7.5, 15, 30, or 60 mg/kg. For combination studies, each dose of TAM was followed 4 h later by 13-CRA at doses of 25, 50, 100, or 200 mg/kg. All treatments began on day 12 and were continued for 3 weeks. Results: The median time to two doublings recorded for the control and for 13-CRA and TAM given as single agents at the highest dose were 22.2, 29.2, and 54.7 days, respectively. In combination, 100 and 200 mg/kg 13-CRA with 7.5 mg/kg TAM resulted in a delay in tumor growth at least as high as that achieved with highest-dose TAM alone, but the effect was not synergistic. Pharmacokinetic analysis of 13-CRA was performed in plasma, liver, and tumor from mice bearing 0.5- to 2.0 g carcinomas following a single dose of 100 mg/kg 13-CRA. Results showed that 13-CRA was metabolized differently in various tissues, but concentrations of 13-CRA detected in tumor were in the range reported to be active in vitro. all-trans-Retinoic acid (ATRA) concentrations were about 5% of the 13-CRA concentrations detected in plasma, 68% of those found in liver, and 20% of those found in tumor. 4-oxo-CRA represented between 2% and 10% of 13-CRA concentrations detected in plasma and liver but was not detected in tumor. Furthermore there was no difference in peak plasma 13-CRA concentrations found in the same tissues at 30 min after a single dose or after the eighth dose of 100 mg/kg 13-CRA or 13-CRA and TAM. Mean 13-CRA concentrations detected in liver and tumor were 50–90% and 16–30% of plasma peak concentrations, respectively. No difference in 4-oxo-CRA concentration was observed between the treatment groups. Conclusions: These data suggest that 13-CRA is not effective against established human breast tumor xenografts despite the stability of the pharmacokinetics of 13-CRA and the generation of ATRA as a metabolite. The addition of 13-CRA to TAM did not improve the efficacy of TAM against these estrogen-receptor-positive xenografts.

Antitumor activity, distribution, and metabolism of 13-cis-retinoic acid as a single agent or in combination with tamoxifen in established human MCF-7 xenografts in mice.

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Phase I clinical trial of all-trans-retinoic acid with correlation of its pharmacokinetics and pharmacodynamics

Antitumor activity, distribution, and metabolism of 13-cis-retinoic acid as a single agent or in combination with tamoxifen in established human MCF-7 xenografts in mice.