Nerve-Sparing Laparoscopic Cystoprostatectomy Based on Inferior Hypogastric Plexus Dissection: Our Initial Experience.

INTRODUCTION: The aim of this study was to implement our technique for the initial dissection of the inferior hypogastric plexus and protection of the autonomic nerve supply to the corpora cavernosa in laparoscopic radical cystoprostatectomy with an orthotopic ileal neobladder and report the initial outcomes. METHODS: Eleven normally potent patients with preoperative cT2N0 bladder cancer who underwent bilateral nerve-sparing laparoscopic cystoprostatectomy performed by the same surgeon were selected from May 2018 to September 2020. In this procedure, the anterior part of the inferior hypogastric plexus was dissected first between the prehypogastric nerve fascia and rectal proper fascia medial to the distal ureter. Then the Denonvilliers' fascia and the nerves around the prostate were preserved according to current intrafascial principles. The preliminary operative, oncologic, and functional results are presented. RESULTS: The median follow-up duration was 18 months. We observed early and late complications in 5 patients, but none exceeded grade III. Of the 11 patients, ten gained daytime continence (90.9%), and 8 (72.7%) showed nocturnal continence at the last follow-up. Regarding postoperative potency, 10 of the 11 patients (90.9%) remained potent with or without oral medications, excluding one who had partial tumescence but did not follow our recommendations regarding medication use. No local recurrence or positive surgical margins were noted. CONCLUSION: In addition to emphasizing our cavernosal nerve-sparing procedure, this report on the precise dissection and protection of the inferior hypogastric plexus could be of clinical significance, providing potentially ideal short-term functional results.

Initial Experience with the Comprehensive Modified Laparoscopic Pyeloplasty Technique Based on Membrane Anatomy for Treating Ureteropelvic Junction Obstruction.

OBJECTIVE: The aim of the objective was to present our initial experience and evaluate the feasibility of the novel comprehensive modified laparoscopic pyeloplasty (CMLP) technique based on membrane anatomy. MATERIALS AND METHODS: Forty-eight patients underwent CMLP from February 2016 to October 2020. CMLP involves the following: dissection of the ureter was based on the fascia or fusion fascia formed by embryonic development. The ureter was separated from the ureteral sheath, and the pelvis and ureter were incised with incomplete amputation. The first stitch was placed between the lower point of the spatulated ureter and the lowest corner of the renal pelvis to ensure correct orientation of the anastomosis; anastomosis of the renal pelvis and ureter was performed using the touchless technique. RESULTS: All CMLPs were completed successfully without conversion. The mean overall operating time was 230.96 min. The median estimated blood loss was 50.00 (interquartile range 20.00-57.50) mL. The average postoperative hospital stay was 9.31 days. The average follow-up time was 24.73 months. No major complications occurred. In 1 case, revision laparoscopic pyeloplasty was performed, but the obstruction persisted after double J stent removal, so ultimately, the double J stent required regular replacement. Another asymptomatic patient with hydronephrosis experienced failed treatment and is still under follow-up. The overall success rate was 95.83% (46/48). The success rate in patients with recurrent ureteropelvic junction obstruction (UPJO) was 87.5% (7/8). CONCLUSIONS: CMLP is a practical and effective treatment option for UPJO with a high success rate. An advantage of CMLP is the clear surgical field.

The applied research of MRI with ASSET-EPI-FLAIR combined with 3D TOF MRA sequences in the assessment of patients with acute cerebral infarction.

Background To extend the time window for thrombolysis, reducing the time for diagnosis and detection of acute cerebral infarction seems to be warranted. Purpose To evaluate the feasibility of implementing an array spatial sensitivity technique (ASSET)-echo-planar imaging (EPI)-fluid attenuated inversion recovery (FLAIR) (AE-FLAIR) sequence into an acute cerebral infarction magnetic resonance (MR) evaluation protocol, and to assess the diagnostic value of AE-FLAIR combined with three-dimensional time-of-flight MR angiography (3D TOF MRA). Material and Methods A total of 100 patients (68 men, 32 women; age range, 44-82 years) with acute cerebral infarction, including 50 consecutive uncooperative and 50 cooperative patients, were evaluated with T1-weighted (T1W) imaging, T2-weighted (T2W) imaging, FLAIR, diffusion-weighted imaging (DWI), 3D TOF, EPI-FLAIR, and AE-FLAIR. Conventional FLAIR, EPI-FLAIR, and AE-FLAIR were assessed by two observers independently for image quality. The optimized group (AE-FLAIR and 3D TOF) and the control group (T1W imaging, T2W imaging, conventional FLAIR, DWI, and 3D TOF) were compared for evaluation time and diagnostic accuracy. Results One hundred and twenty-five lesions were detected and images having adequate diagnostic image quality were in 73% of conventional FLAIR, 62% of EPI-FLAIR, and 89% of AE-FLAIR. The detection time was 12 ± 1 min with 76% accuracy and 4 ± 0.5 min with 100% accuracy in the control and the optimized groups, respectively. Inter-observer agreements of κ = 0.78 and κ = 0.81 were for the optimized group and control group, respectively. Conclusion With reduced acquisition time and better image quality, AE-FLAIR combined with 3D TOF may be used as a rapid diagnosis tool in patients with acute cerebral infarction, especially in uncooperative patients.

CIP2A mediates prostate cancer progression via the c-MYC signaling pathway.

Recent evidence suggests that cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that acts as a novel therapeutic target in a variety of tumors. In this study, we investigated the clinical significance of CIP2A and its function in our large collection of prostate samples. Between August 2000 and December 2013, 126 patients with histologically confirmed PCa and 92 with benign prostate hyperplasia (BPH) were recruited into the study. Quantitative RT-PCR, Western blot, and immunohistochemistry analyses were used to quantify CIP2A expression in PCa clinical samples and cell lines. The relationships between CIP2A expression and clinicopathological features were analyzed. The functional role of CIP2A in PCa cells was evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation and invasion. High expression of CIP2A staining was 86.51 % (109/126) in 126 cases of PCa and 17.39 % (16/92) in 92 cases of BPH, and the difference of CIP2A expression between PCa and BPH was statistically significant. CIP2A was significantly elevated in all five PCa cell lines when compared to the RWPE-1 cells at both the messenger RNA (mRNA) and protein levels. Silencing of CIP2A inhibited the proliferation of DU-145 cells which have a relatively high level of CIP2A in a time- and concentration-dependent manner, and the invasion and migration of DU-145 cells were distinctly suppressed. Furthermore, CIP2A knockdown led to substantial reductions in c-Myc levels in PCa cell lines, but no significant change in phosphorylated Akt expression after CIP2A knockdown in DU-145 cells. Our data suggest that the pathogenesis of human PCa maybe mediated by CIP2A, and CIP2A inhibition treatment may provide a promising strategy for the antitumor therapy of PCa, and thus CIP2A could represent selective targets for the molecularly targeted treatments of PCa.

CIP2A mediates prostate cancer progression via the c-Myc signaling pathway.

Recent evidence suggests that cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein that acts as a novel therapeutic target in a variety of tumors. In this study, we investigated the clinical significance of CIP2A and its function in our large collection of prostate samples. Between August 2000 and December 2013, 126 patients with histologically confirmed prostate cancer (PCa) and 92 with benign prostate hyperplasia (BPH) were recruited into the study. Quantitative real-time PCR (RT-PCR), Western blot, and immunohistochemistry analyses were used to quantify CIP2A expression in PCa clinical samples and cell lines. The relationships between CIP2A expression and clinicopathological features were analyzed. The functional role of CIP2A in PCa cells was evaluated by small interfering RNA-mediated depletion of the protein followed by analyses of cell proliferation and invasion. High expression of CIP2A staining was 86.51 % (109/126) in 126 cases of PCa and 17.39 % (16/92) in 92 cases of BPH; the difference of CIP2A expression between PCa and BPH was statistically significant. CIP2A was significantly elevated in all five PCa cell lines when compared to the RWPE-1 cells at both the messenger RNA (mRNA) and protein levels. Silencing of CIP2A inhibited the proliferation of DU-145 cells which have a relatively high level of CIP2A in a time- and concentration-dependent manner, and the invasion and migration of DU-145 cells were distinctly suppressed. Furthermore, CIP2A knockdown led to substantial reductions in c-Myc levels in DU-145 cells, but no significant change in phosphorylated Akt expression after CIP2A knockdown in DU-145 cells. Our data suggest that the pathogenesis of human PCa maybe mediated by CIP2A, and CIP2A inhibition treatment may provide a promising strategy for the antitumor therapy of PCa, and thus, CIP2A could represent selective targets for the molecularly targeted treatments of PCa.

Blood metabolites mediate the causal relationship between circulating CX3CL1 levels and prostate cancer: A 2-step Mendelian randomization study.

Chemokines influence the progression of prostate cancer (PCa) through multiple mechanisms. However, the effect of C-X3-C chemokine ligand 1 (CX3CL1) on PCa risk remains controversial. Our study aimed to investigate whether circulating CX3CL1 is causally associated with PCa and to identify metabolites that have mediating effects using the 2-step bidirectional Mendelian randomization (MR) analysis process. Inverse variance weighting (IVW) results were used as the primary observations, while additional sensitivity analyses were conducted. For each standard deviation increase exhibited by the circulating CX3CL1 levels, the risk of PCa was reduced by 0.4% (IVW: OR = 0.996, [95% CI = 0.994-0.998], P < .001), and blood alliin levels increased by 19% (IVW: OR = 1.185, [95% CI = 1.01-1.54], P = .003). For each standard deviation increase in the blood alliin levels, the risk of PCa was reduced by 0.1% (IVW: OR = 0.999, [95% CI = 0.997-0.999], P = .03). Therefore, the protective effect of circulating CX3CL1 on PCa may be mediated by blood alliin levels (mediated proportion = 6.7%). The results supported the notion that high levels of circulating CX3CL1 indicate a lower PCa risk and the idea that the food-derived antioxidant alliin may mediate this association. We emphasize that the use of CX3CL1 as a protective factor against PCa may provide new strategies for PCa prevention and care in the future.

Development and validation of a prognostic nomogram for predicting cancer-specific survival in patients with metastatic clear cell renal carcinoma: A study based on SEER database.

Objectives: Clear cell renal cell carcinoma (ccRCC) is highly prevalent, prone to metastasis, and has a poor prognosis after metastasis. Therefore, this study aimed to develop a prognostic model to predict the individualized prognosis of patients with metastatic clear cell renal cell carcinoma (mccRCC). Patients and Methods: Data of 1790 patients with mccRCC, registered from 2010 to 2015, were extracted from the Surveillance, Epidemiology and End Results (SEER) database. The included patients were randomly divided into a training set (n = 1253) and a validation set (n = 537) based on the ratio of 7:3. The univariate and multivariate Cox regression analyses were used to identify the important independent prognostic factors. A nomogram was then constructed to predict cancer specific survival (CSS). The performance of the nomogram was internally validated by using the concordance index (C-index), calibration plots, receiver operating characteristic curves, net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision curve analysis (DCA). We compared the nomogram with the TNM staging system. Kaplan-Meier survival analysis was applied to validate the application of the risk stratification system. Results: Diagnostic age, T-stage, N-stage, bone metastases, brain metastases, liver metastases, lung metastases, chemotherapy, radiotherapy, surgery, and histological grade were identified as independent predictors of CSS. The C-index of training and validation sets are 0.707 and 0.650 respectively. In the training set, the AUC of CSS predicted by nomogram in patients with mccRCC at 1-, 3- and 5-years were 0.770, 0.758, and 0.757, respectively. And that in the validation set were 0.717, 0.700, and 0.700 respectively. Calibration plots also showed great prediction accuracy. Compared with the TNM staging system, NRI and IDI results showed that the predictive ability of the nomogram was greatly improved, and DCA showed that patients obtained clinical benefits. The risk stratification system can significantly distinguish the patients with different survival risks. Conclusion: In this study, we developed and validated a nomogram to predict the CSS rate in patients with mccRCC. It showed consistent reliability and clinical applicability. Nomogram may assist clinicians in evaluating the risk factors of patients and formulating an optimal individualized treatment strategy.

Improved pharmacokinetics and efficacy of a highly stable nanoliposomal vinorelbine.

Effective liposomal formulations of vinorelbine (5' nor-anhydro-vinblastine; VRL) have been elusive due to vinorelbine's hydrophobic structure and resulting difficulty in stabilizing the drug inside the nanocarrier. Triethylammonium salts of several polyanionic trapping agents were used initially to prepare minimally pegylated nanoliposomal vinorelbine formulations with a wide range of drug release rates. Sulfate, poly(phosphate), and sucrose octasulfate were used to stabilize vinorelbine intraliposomally while in circulation, with varying degrees of effectiveness. The release rate of vinorelbine from the liposomal carrier was affected by both the chemical nature of the trapping agent and the resulting drug-to-lipid ratio, with liposomes prepared using sucrose octasulfate displaying the longest half-life in circulation (9.4 h) and in vivo retention in the nanoparticle (t(1/2) = 27.2 h). Efficacy was considerably improved in both a human colon carcinoma (HT-29) and a murine (C-26) colon carcinoma model when vinorelbine was stably encapsulated in liposomes using triethylammonium sucrose octasulfate. Early difficulties in preparing highly pegylated formulations were later overcome by substituting a neutral distearoylglycerol anchor for the more commonly used anionic distearoylphosphatidylethanolamine anchor. The new pegylated nanoliposomal vinorelbine displayed high encapsulation efficiency and in vivo drug retention, and it was highly active against human breast and lung tumor xenografts. Acute toxicity of the drug in immunocompetent mice slightly decreased upon encapsulation in liposomes, with a maximum tolerated dose of 17.5 mg VRL/kg for free vinorelbine and 23.8 mg VRL/kg for nanoliposomal vinorelbine. Our results demonstrate that a highly active, stable, and long-circulating liposomal vinorelbine can be prepared and warrants further study in the treatment of cancer.

Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy.

Liposome formulations of camptothecins have been actively pursued because of the potential for significant pharmacologic advantages from successful drug delivery of this important class of anticancer drugs. We describe nanoliposomal CPT-11, a novel nanoparticle/liposome construct containing CPT-11 (irinotecan) with unprecedented drug loading efficiency and in vivo drug retention. Using a modified gradient loading method featuring a sterically hindered amine with highly charged, multivalent anionic trapping agents, either polymeric (polyphosphate) or nonpolymeric (sucrose octasulfate), liposomes were capable of entrapping CPT-11 at extremely high drug-to-lipid ratios (>800 g CPT-11/mol phospholipid) and retaining encapsulated drug in vivo with a half-life of drug release in the circulation of 56.8 hours. CPT-11 was also protected from hydrolysis to the inactive carboxylate form and from metabolic conversion to SN-38 while circulating. The maximum tolerated dose in normal mice was determined to be 80 mg/kg for free CPT-11 and >320 mg/kg for nanoliposomal CPT-11. Nanoliposomal CPT-11 showed markedly superior efficacy when compared with free CPT-11 in human breast (BT474) and colon (HT29) cancer xenograft models. This study shows that intraliposomal stabilization of CPT-11 using a polymeric or highly charged, nonpolymeric polyanionic trapping agent results in a markedly active antitumor agent with low toxicity.

Epidermal growth factor receptor-targeted immunoliposomes significantly enhance the efficacy of multiple anticancer drugs in vivo.

We previously reported the development of epidermal growth factor receptor (EGFR)-targeted immunoliposomes that bind and internalize in tumor cells which overexpress EGFR and/or mutant EGFR variant III (EGFRvIII), enabling intracellular delivery of potent anticancer agents in vitro. We now describe in vivo proof-of-concept for this approach for the delivery of multiple anticancer drugs in EGFR-overexpressing tumor models. Anti-EGFR immunoliposomes were constructed modularly with Fab' fragments of cetuximab (IMC-C225), covalently linked to liposomes containing probes and/or anticancer drugs. Pharmacokinetic and biodistribution studies confirmed long circulation times (t(1/2) = 21 hours) and efficient accumulation in tumors (up to 15% ID/g) irrespective of the presence of the targeting ligand. Although total accumulations of anti-EGFR immunoliposomes and nontargeted liposomes in EGFR-overexpressing tumors were comparable, only immunoliposomes internalized extensively within tumor cells (92% of analyzed cells versus <5% for nontargeted liposomes), indicating different mechanisms of delivery at the cellular level. In vivo therapy studies in a series of xenograft models featuring overexpression of EGFR and/or EGFRvIII showed the superiority of immunoliposomal delivery of encapsulated drugs, which included doxorubicin, epirubicin, and vinorelbine. For each of these drugs, anti-EGFR immunoliposome delivery showed significant antitumor effects and was significantly superior to all other treatments, including the corresponding free or liposomal drug (P < 0.001-0.003). We conclude that anti-EGFR immunoliposomes provide efficient and targeted drug delivery of anticancer compounds and may represent a useful new treatment approach for tumors that overexpress the EGFR.

Enhanced pharmacodynamic and antitumor properties of a histone deacetylase inhibitor encapsulated in liposomes or ErbB2-targeted immunoliposomes.

ErbB2-overexpressing human cancers represent potentially sensitive targets for therapy by candidate histone deacetylase (HDAC) inhibitors as we have shown that HDAC inhibitors can selectively reduce ErbB2 expression by repressing the ErbB2 promoter and accelerating the decay of cytoplasmic ErbB2 transcripts. To extend these in vitro findings and enhance the in vivo pharmacodynamic properties of HDAC inhibitors, we stably encapsulated a potent hydroxamate-based HDAC inhibitor (LAQ824) within long-circulating liposomes (Ls-LAQ824) and immunoliposomes (ILs-LAQ824) bearing >10,000 LAQ824 molecules per nanovesicle. Liposomal LAQ824 exhibits prolonged in vivo stability and, unlike free LAQ824, circulates with a half-life of 10.8 hours following a single i.v. injection. Three weekly i.v. injections of 20 to 25 mg/kg Ls-LAQ824 in nude mice with ErbB2 overexpressing BT-474 breast tumor xenografts significantly impairs tumor growth, and administration of ErbB2-targeted ILs-LAQ824 may further improve this antitumor activity. Studies of tumor-bearing mice 24 hours after single treatment indicate that: (a) >10% of injected liposomal LAQ824 is still circulating (whereas free LAQ824 is undetectable in the blood after 15 minutes); and (b) tumor uptake of Ls-LAQ824 and ILs-LAQ824 is >3% injected drug per gram of tumor, producing levels of acetylated tumor histones that are 5- to 10-fold increased over those following free LAQ824 or saline treatments and resulting in concordantly reduced levels of tumor ErbB2 mRNA. These preclinical results support the clinical evaluation of HDAC inhibitors against ErbB2-overexpressing malignancies, and further indicate that encapsulation into targeted and nontargeted liposomes substantially improves the in vivo pharmacokinetics, tumor uptake, and antitumor properties of hydroxamate-based HDAC inhibitors.

Upregulation of centromere protein H is associated with progression of renal cell carcinoma.

Centromere protein H (CENPH), one of the essential component of active kinetochore, plays an important role in carcinogenesis of many cancer types. However, its expression signature and prognostic significance of renal cell carcinoma (RCC) are unclear. In the present study, we concluded that the expression of CENPH was prominently upregulated in RCC specimens and three RCC cell lines (ACHN, 786-O and A704). Immunohistochemical analysis revealed that RCCs exhibited higher levels of CENPH expression than normal renal tissues in paraffin-embedded archival specimens. Further statistical analysis suggested the upregulation of CENPH was positively correlated with the Fuhrman grade (P = 0.001), distant metastasis (P = 0.024) and clinical stage (P = 0.014). In addition, the CENPH served as an independent predictor of overall survival of RCC patients in multivariate analysis (P = 0.018). Furthermore, our in vitro assays of RCC cell lines indicated that knockdown of CENPH reduced cell proliferation, inhibited cell growth, and increased cell apoptosis. In conclusion, our data suggest that CENPH is a novel molecule involved in RCC progression, which provides a potential biomarker and therapeutic target.

A recommended technique of renal vein anastomosis in rat kidney transplantation for trainee.

BACKGROUND: Various rat kidney transplantation models have been introduced over the decades and the study on the models seems to lack novelty and necessity. However, vascular anastomosis, especially renal vein, is still very difficult for trainees. The aim of this study was to provide the modified renal venous anastomosis of rat kidney transplantation to substitute the current method for trainees. METHODS: Male Wistar rats were used as donors and recipients, respectively. Left orthotopic transplantation was performed with a modified technique of renal vein anastomosis, combining the end-to-end sutures with epidural catheter. Meanwhile, the survival rate, warm ischemia time, renal venous anastomosis time, and complications were recorded to evaluate the merits of the modified technique compared with the current recommended technique of rat renal vein. Two trainees took part in the learning of the models in two methods for performing 30 operations, respectively. RESULTS: The difference in warm ischemia time (from (57.25 ± 7.30) minutes in the first 10 operations to (30.05 ± 1.85) minutes in the third 10 operations) and renal vein anastomosis time (from (32.80 ± 3.80) minutes in the first 10 operations to (19.30 ± 0.98) minutes in the third 10 operations) was significantly short (P < 0.01) and the survival rate was statistically high (from (25 ± 7)% in the first 10 operations to 70% in the third 10 operations) in equal number of operations (P < 0.01) by comparing with the current recommended method ((47.60 ± 7.19) minutes to (22.8 ± 1.85) minutes, (22.40 ± 3.10) minutes to (9.95 ± 1.50) minutes, 45%± 7% to 80%± 0, respectively). The intraoperative complications and postoperative complications of renal venous anastomosis were also significantly decreased (P < 0.01). CONCLUSIONS: The technique with epidural catheter can shorten the learning curve of the trainee learning rat kidney transplantation. It may replace the currently recommended technique of rat renal vein for trainees.

Development of a highly stable and targetable nanoliposomal formulation of topotecan.

Topotecan (TPT), a highly active anticancer camptothecin drug, would benefit from nanocarrier-mediated site-specific and intracellular delivery because of a labile lactone ring whose hydrolysis inactivates the drug, poor cellular uptake resulting from both lactone hydrolysis and a titratable phenol hydroxyl, and the schedule-dependency of its efficacy due to its mechanism of action. We have encapsulated topotecan in liposomes using transmembrane gradients of triethylammonium salts of polyphosphate (Pn) or sucroseoctasulfate (SOS). Circulation lifetimes were prolonged, and the rate of drug release in vivo depended on the drug load (T(1/2)=5.4 h vs. 11.2 h for 124 and 260 g TPT/mol PL, respectively) and the nature of intraliposomal drug complexing agent used to stabilize the nanoliposome formulation (T(1/2)=11.2 h vs. 27.3 h for Pn and SOS, respectively). Anti-EGFR and anti-HER2-immunoliposomal formulations dramatically increased uptake of topotecan compared to nontargeted nanoliposomal topotecan and poorly permeable free topotecan in receptor-overexpressing cancer cell lines, with a corresponding increase in cytotoxicity in multiple breast cancer cell lines and improved antitumor activity against HER2-overexpressing human breast cancer (BT474) xenografts. We conclude that stabilization of topotecan in nanoliposomes significantly improves the targetability and pharmacokinetic profile of topotecan, allowing for highly active formulations against solid tumors and immunotargeting to cancer-overexpressing cell surface receptors.

Characterization of highly stable liposomal and immunoliposomal formulations of vincristine and vinblastine.

PURPOSE: Liposome and immunoliposome formulations of two vinca alkaloids, vincristine and vinblastine, were prepared using intraliposomal triethylammonium sucroseoctasulfate and examined for their ability to stabilize the drug for targeted drug delivery in vivo. METHODS: The pharmacokinetics of both the encapsulated drug (vincristine or vinblastine) and liposomal carrier were examined in Sprague Dawley rats, and the in vivo drug release rates determined. Anti-HER2 immunoliposomal vincristine was prepared from a human anti-HER2/neu scFv and studied for targeted cytotoxic activity in cell culture, and antitumor efficacy in vivo. RESULTS: Nanoliposome formulations of vincristine and vinblastine demonstrated similar pharmacokinetic profiles for the liposomal carrier, but increased clearance for liposome encapsulated vinblastine (t (1/2) = 9.7 h) relative to vincristine (t (1/2) = 18.5 h). Immunoliposome formulations of vincristine targeted to HER2 using an anti-HER2 scFv antibody fragment displayed a marked enhancement in cytotoxicity when compared to non-targeted liposomal vincristine control; 63- or 253-fold for BT474 and SKBR3 breast cancer cells, respectively. Target-specific activity was also demonstrated in HER2-overexpressing human tumor xenografts, where the HER2-targeted formulation was significantly more efficacious than either free vincristine or non-targeted liposomal vincristine. CONCLUSIONS: These results demonstrate that active targeting of solid tumors with liposomal formulations of vincristine is possible when the resulting immunoliposomes are sufficiently stabilized.

Clinical development of histone deacetylase inhibitors as anticancer agents.

Acetylation is a key posttranslational modification of many proteins responsible for regulating critical intracellular pathways. Although histones are the most thoroughly studied of acetylated protein substrates, histone acetyltransferases (HATs) and deacetylases (HDACs) are also responsible for modifying the activity of diverse types of nonhistone proteins, including transcription factors and signal transduction mediators. HDACs have emerged as uncredentialed molecular targets for the development of enzymatic inhibitors to treat human cancer, and six structurally distinct drug classes have been identified with in vivo bioavailability and intracellular capability to inhibit many of the known mammalian members representing the two general types of NAD+-independent yeast HDACs, Rpd3 (HDACs 1, 2, 3, 8) and Hda1 (HDACs 4, 5, 6, 7, 9a, 9b, 10). Initial clinical trials indicate that HDAC inhibitors from several different structural classes are very well tolerated and exhibit clinical activity against a variety of human malignancies; however, the molecular basis for their anticancer selectivity remains largely unknown. HDAC inhibitors have also shown preclinical promise when combined with other therapeutic agents, and innovative drug delivery strategies, including liposome encapsulation, may further enhance their clinical development and anticancer potential. An improved understanding of the mechanistic role of specific HDACs in human tumorigenesis, as well as the identification of more specific HDAC inhibitors, will likely accelerate the clinical development and broaden the future scope and utility of HDAC inhibitors for cancer treatment.