Fig 1: Expression of CHST11, CHST3 and CHST7 in epithelium and stroma.(A) In the normal and malignant prostate stromal and epithelial tissues obtained by laser capture -microdissection (LCM), mRNA expression of the chondroitin-4-sulfotransferase CHST11 is significantly greater in the stroma, both normal and malignant, than in the epithelium (p < 0.001, n = 6). CHST expression is significantly lower in the malignant epithelium, compared to the normal epithelium (p < 0.001; n = 6). (B) In cultured normal prostate stromal cells, CHST11 expression is significantly more than in epithelial cells (p < 0.001; n = 6). ARSB silencing by siRNA leads to declines in CHST11 expression in both stromal and epithelial cells (p < 0.001; n = 6). (C) In the normal and malignant prostate stromal and epithelial tissues obtained by LCM, the mRNA expression of CHST3, a chondroitin-6-sulfotransferase, is higher in the epithelium than in the stroma, and similar in normal and malignant tissue (p < 0.001, n = 6). CHST7, another chondroitin 6-sulfotransferase, is not significantly different in stroma vs. epithelium or in malignant vs. normal tissue. (D) There are no significant differences in CHST7 expression between the prostate stromal and epithelial cells when ARSB is silenced. (E) The expression of CHST11 is increased in both the normal human prostate epithelial cells (CRL-2850) and in the malignant PC-3 cell line (CRL-1435, ATCC) following exposure to exogenous TGF-β (10 ng/ml × 24 h; p < 0.001, n = 3). This is consistent with previous data about the effect of TGF-β on CHST11 expression and shows that the pathway for expression is intact in the epithelial cells [50]. *** represents p ≤ 0.001 and greater than control; ### represents p ≤ 0.001 and less than control. [ARSB = arylsulfatase B; CHST = chondroitin sulfotransferase; LCM = laser-capture microdissection; PC-3 = metastatic prostate cell line; PEC = prostate epithelial cell; si = siRNA; TGF-β = transforming growth factor β]
Fig 2: Improved efficacy in urologic carcinoma xenografts administered intratumoral (IT) large surface area microparticle docetaxel (LSAM-DTX) compared to intravenous (IV) docetaxel. a 786-O (ATCC® CRL-1932™) xenografts in immunodeficient Sprague–Dawley (Rag2/Il2rg null (SRG™) female rats; n = 3/group; treatment was initiated 7 days after tumor implant when group mean TVs ranged from 336 to 427 mm3. IV docetaxel administered for two cycles of 5 mg/kg to 2 of 3 animals resulted in one immediate death due to cessation of respiration and one animal with temporary loss of respiration and prolonged recovery from anesthesia. Due to this toxicity, the third animal in the group was not administered a second cycle of IV docetaxel and the final cycle administered to both remaining animals was reduced to 2.5 mg/kg. Data plotted through point when ≥ 50% of animals in the group survived. Due to small number of animals per group, statistical analysis was not performed. b UM-UC-3 (ATCC® CRL-1749™) xenografts in immunodeficient (Hsd:Athymic Nude-Foxn1nu) female mice; n = 9 or 10/group; treatment was initiated 18 days after tumor implant when group mean TVs ranged from 161 to 164 mm3. ****p < 0.0001 for all treatment groups vs. 3 × IT vehicle (day 34); #p < 0.01 for 3 × IV docetaxel vs. 2 × and 3 × LSAM-DTX (Day 59). Data plotted through point when first animal in the group died. c PC-3 xenografts (ATCC® CRL-1435™) in immunodeficient (NCr nu/nu (Crl:NU(NCr)-Foxn1nu)) female mice; n = 10/group; treatment was initiated 26 days after tumor implant when group mean TVs ranged from 136 to 141 mm.3. ****p < 0.0001 for all treatment groups vs. 3 × IT vehicle (day 69). Data plotted through point when ≥ 50% of animals in the group survived. Statistical significance was determined using one-way ANOVA with Dunnett’s post-test analysis. In all studies, red triangles designate days of treatment. Adapted with permission from [9]
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