Cellular Uptake and Efflux of Palbociclib In Vitro in Single Cell and Spheroid Models.

Adequate drug distribution through tumors is essential for treatment to be effective. Palbociclib is a cyclin-dependent kinase 4/6 inhibitor approved for use in patients with hormone receptor positive, human epidermal growth factor receptor 2 negative metastatic breast cancer. It has unusual physicochemical properties, which may significantly influence its distribution in tumor tissue. We studied the penetration and distribution of palbociclib in vitro, including the use of multicellular three-dimensional models and mathematical modeling. MCF-7 and DLD-1 cell lines were grown as single cell suspensions (SCS) and spheroids; palbociclib uptake and efflux were studied using liquid chromatography-tandem mass spectrometry. Intracellular concentrations of palbociclib for MCF-7 SCS (C max 3.22 µM) and spheroids (C max 2.91 µM) were 32- and 29-fold higher and in DLD-1, 13- and 7-fold higher, respectively, than the media concentration (0.1 µM). Total palbociclib uptake was lower in DLD-1 cells than MCF-7 cells in both SCS and spheroids. Both uptake and efflux of palbociclib were slower in spheroids than SCS. These data were used to develop a mathematical model of palbociclib transport that quantifies key parameters determining drug penetration and distribution. The model reproduced qualitatively most features of the experimental data and distinguished between SCS and spheroids, providing additional support for hypotheses derived from the experimental data. Mathematical modeling has the potential for translating in vitro data into clinically relevant estimates of tumor drug concentrations. SIGNIFICANCE STATEMENT: This study explores palbociclib uptake and efflux in single cell suspension and spheroid models of cancer. Large intracellular concentrations of palbociclib are found after drug exposure. The data from this study may aid understanding of the intratumoural pharmacokinetics of palbociclib, which is useful in understanding how drug distributes within tumor tissue and optimizing drug efficacy. Biomathematical modelling has the potential to derive intratumoural drug concentrations from plasma pharmacokinetics in patients.

Clinical and US findings in prostate cancer: patients with normal prostate-specific antigen levels.

PURPOSE: To determine guidelines for biopsy in men with normal prostate-specific antigen (PSA) levels and suspected prostate cancer. MATERIALS AND METHODS: The clinical-sonographic features of 91 lesions of reduced echogenicity in 83 men with normal PSA levels who underwent transrectal ultrasound-guided biopsy were analyzed. RESULTS: Sixteen men (19%) had cancer, two with bilateral foci, and four had prostatic intraepithelial neoplasia (PIN). Fourteen of 47 discrete hypoechoic lesions yielded cancer or PIN versus only five of 44 ill-defined vaguely hypoechoic lesions (P = .03). Fifteen of 18 malignant lesions exceeded 1 cm in longest dimension. In 47 men, sonographic and digital rectal examination (DRE) findings corresponded; 17 (36%) had cancer or PIN. By contrast, of 36 patients with differing sonographic and DRE findings, only three (8%) had malignancy at biopsy (P < .01). CONCLUSION: Predictors of malignancy at sonography of the peripheral prostate gland in men with normal PSA levels include (a) lesion size, (b) degree and focality of hypoechogenicity, and (c) correspondence with the site of DRE abnormality.

Isolation and characteristics of small intestinal lamina propria cells from normal and nematode (Nippostrongylus brasiliensis)-infected rats.

Intestinal lamina propria (LP) cells were isolated from normal or nematode (Nippostrongylus brasiliensis)-infected rats. At certain times after infection (days 11-17), viable cell recoveries from infected rats were lower, whereas at other times (days 20-50), they were significantly greater than those from normal rats. The frequencies of lymphocytes, plasma cells, eosinophils, mast cells and macrophages from LP differed between normal and infected rats, and the histamine content did also. However, spontaneous 3H-uridine and 3H-thymidine incorporation and the number of cells with cytoplasmic immunoglobulin were similar. LP cells from normal rats were unresponsive to the mitogens phytohemagglutinin, concanavalin A and pokeweed. 125I-deoxyuridine-radiolabeled LP lymphoblasts from normal rats were widely distributed in recipients 22-24 h after transfer and showed no selective predilection to return to the intestine. The isolation procedure can be used to study intestinal LP cells from normal or diseased animals.