Multiple Solid Tumor Types Research Articles

Synergistic activity of ixabepilone plus other anticancer agents: preclinical and clinical evidence.

Ixabepilone demonstrates marked synergistic activity in combination with capecitabine, which served as the rationale for the evaluation of this combination in the clinic. Ixabepilone plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer (MBC) progressing after treatment with an anthracycline and a taxane; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy. An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab, bevacizumab, brivanib, and cetuximab; with immune-modulating agents such as anti-CTLA-4 antibody; and with other chemotherapy drugs such as irinotecan and epirubicin. Notably, experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab-paclitaxel combined with bevacizumab. These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in HER2-positive breast cancer; with bevacizumab in breast cancer, endometrial cancer, renal cancer, and non-small cell lung cancer (NSCLC); with cetuximab in breast cancer, NSCLC, and pancreatic cancer; and with brivanib, dasatinib, sorafinib, sunitinib, or vorinostat in MBC. Preliminary results from several of these trials suggest that ixabepilone-based combinations have promising anticancer activity.

Gene therapy using genetically modified lymphocytes targeting VEGFR-2 inhibits the growth of vascularized syngenic tumors in mice

Immunotherapies based on adoptive cell transfer are highly effective in the treatment of metastatic melanoma, but the use of this approach in other cancer histologies has been hampered by the identification of appropriate target molecules. Immunologic approaches targeting tumor vasculature provide a means for the therapy of multiple solid tumor types. We developed a method to target tumor vasculature, using genetically redirected syngeneic or autologous T cells. Mouse and human T cells were engineered to express a chimeric antigen receptor (CAR) targeted against VEGFR-2, which is overexpressed in tumor vasculature and is responsible for VEGF-mediated tumor progression and metastasis. Mouse and human T cells expressing the relevant VEGFR-2 CARs mediated specific immune responses against VEGFR-2 protein as well as VEGFR-2-expressing cells in vitro. A single dose of VEGFR-2 CAR-engineered mouse T cells plus exogenous IL-2 significantly inhibited the growth of 5 different types of established, vascularized syngeneic tumors in 2 different strains of mice and prolonged the survival of mice. T cells transduced with VEGFR-2 CAR showed durable and increased tumor infiltration, correlating with their antitumor effect. This approach provides a potential method for the gene therapy of a variety of human cancers.

Monoclonal Antibodies in Solid Tumours

Monoclonal antibodies (mAbs) have become an integral part of therapeutic strategies used to treat solid tumours. Directed against membrane-bound receptors or extracellular ligands with high specificity, they target elements upstream in the signal transduction pathways that contribute to malignant growth, proliferation, survival, angiogenesis and spread. Several mAbs have now received regulatory approval - trastuzumab, cetuximab, panitumumab, bevacizumab and catumaxomab-across multiple solid tumour types, including breast, colorectal, and non-small cell lung cancers, amongst others. Despite these successes there have been ample disappointments, which in turn is stimulating ongoing research and development efforts. Nevertheless, greater initiative and vision in this development process is needed, from intelligent compound design to enrichment of patient populations during clinical development, biomarker discovery and ultimately tailored, individualised treatment decisions. In this commentary we review those mAbs now in routine use for solid tumours, interesting aspects of their use and future directions.

Abstract A29: Discovery and preclinical to clinical evaluation of biomarkers for Anti-DLL4, a monoclonal antibody targeting cancer stem cells

Abstract Blockade of DLL4 signaling reduces tumor growth in preclinical human xenograft models by disrupting productive angiogenesis and reducing proliferation of tumor cells. Importantly in these models, blocking DLL4 also reduces cancer stem cell (CSC) frequency in multiple solid tumor types. Currently, there exists an important need to identify and evaluate pharmacodynamic biomarkers that indicate the biological activity of agents, such as anti-DLL4, that are in clinical studies. Towards this aim, we used numerous human xenograft models derived from primary human tumors to identify and characterize biomarkers for anti-DLL4. Here, we present data from these studies and describe anti-DLL4 biomarkers in tumors, in hair follicles, and in blood. We show that several vascular-related genes are significantly upregulated by anti-DLL4 in tumors including, Egfl7, Apln, Cldn5, and Notch4. We also demonstrate significant downregulation of CSC gene signatures and modulation of differentiation genesets. A subset of the identified markers were validated at the protein level and also tested in a human skin graft model, where the human tumor is engrafted in a human microenvironment/vasculature. Finally, a DLL4-Notch gene signature was identified that showed a significant association with breast cancer survival using publicly available cancer gene sets. In surrogate tissues, we identified anti-DLL4 biomarkers in blood and in hair follicles. These markers from surrogate tissues were translated into a phase I trial of Anti-DLL4 antibody (OMP-21M18), and an interim analysis of this data demonstrates that OMP-21M18 affects the Notch pathway in patient samples. Citation Information: Clin Cancer Res 2010;16(14 Suppl):A29.

Advances in Targeting Src in the Treatment of Breast Cancer and Other Solid Malignancies

Src, a membrane-associated nonreceptor tyrosine kinase, plays a crucial role in the coordination and facilitation of cell-signaling pathways controlling a wide range of cellular functions, including growth, survival, invasion, adhesion, and migration. Deregulation and increased activity of Src has been observed in multiple human malignancies, prompting the development of specific inhibitors of Src. In preclinical studies, Src inhibitors show antitumor effects in multiple solid tumor types. Recently completed early-phase trials using the inhibitors dasatinib and bosutinib have suggested modest activity as monotherapy in breast and prostate cancer, with potentially greater activity in combination regimens. Given the interaction between Src and the estrogen receptor, ongoing trials are exploring combinations with endocrine therapy. The relationship between Src and the vascular endothelial growth factor receptor also justifies investigation of combinations with angiogenesis inhibitors. Future trials will continue to explore the contribution of Src inhibition with both chemotherapy and targeted agents.

Abstract 4160: Evaluating epithelial-to-mesenchymal transition (EMT) in the EL1-luc/EL1-SV40 T-antigen transgenic mouse model of pancreatic cancer

Abstract Epithelial-to-mesenchymal transition (EMT) is a biological function important in normal cellular processes such as embryonic development and wound healing. In cancer it is thought that the tumor cell machinery can re-activate these normal pathways resulting in more aggressive and invasive tumors. The loss of E-cadherin and the gain of vimentin are hallmarks which identify the process of EMT and have been shown to correlate with poor prognosis in multiple solid tumor types. While many preclinical models are utilized to evaluate mechanisms of tumorigenesis few in vivo models evaluating parameters of EMT have been described. The EL1-luc/EL1-SV40 T-antigen transgenic mouse represents a model of pancreatic cancer whereby mice develop tissue specific, spontaneous and bioluminescent pancreatic tumors. To evaluate whether EMT occurs in the EL1-luc/EL1-SV40 T-antigen model in vivo, we collected primary pancreatic tissue from male mice between 10 and 21 weeks of age. The tissue was formalin fixed, paraffin embedded and then utilized for histopathological endpoints such as Hemotoxylin and Eosin staining as well as immunohistochemistry for markers known to be involved in EMT such as E-cadherin and vimentin. We found the tumors to express both markers and become very heterogeneous over time. In early tumors E-cadherin expression is membrane localized and very high. Over time there are areas of the tumors that have reduced or lost E-cadherin expression. Vimentin expression was highly variable but when present tended to be highly expressed. In many of the later stage tumors there was substantial heterogeneity reflected by the appearance of multiple cell types within a tumor. We utilized the Aperio (Aperio Technologies, Vista, CA) slide scanner and software system to evaluate serial sections of tumor samples and found that in some sections of the tumor E-cadherin is present and vimentin is absent, whereas in other areas of the tumor vimentin is present in the absence of E-cadherin. Additionally, we identified areas of the tumor that seem to be expressing both markers which suggests that the EL1-luc/EL1-SV40 T-antigen transgenic mouse may recapitulate many aspects of EMT observed in vivo, thus offering a model system to study the signaling and molecular changes necessary for this process during cancer progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4160.

Signaling From the Golgi: Mechanisms and Models for Golgi Phosphoprotein 3–Mediated Oncogenesis

Golgi phosphoprotein 3 (GOLPH3; also known as GPP34/GMx33/MIDAS) represents an exciting new class of oncoproteins involved in vesicular trafficking. Encoded by a gene residing on human chromosome 5p13, which is frequently amplified in multiple solid tumor types, GOLPH3 was initially discovered as a phosphorylated protein localized to the Golgi apparatus. Recent functional, cell biological, and biochemical analyses show that GOLPH3 can function as an oncoprotein to promote cell transformation and tumor growth by enhancing activity of the mammalian target of rapamycin, a serine/threonine protein kinase known to regulate cell growth, proliferation, and survival. Although its precise mode of action in cancer remains to be elucidated, the fact that GOLPH3 has been implicated in protein trafficking, receptor recycling, and glycosylation points to potential links of these cellular processes to tumorigenesis. Understanding how these processes may be deregulated and contribute to cancer pathogenesis and drug response will uncover new avenues for therapeutic intervention.

Effects of An Omega 3 Fatty Acid Supplement Consumption On Platelet Aggregation Tests in Patients Low Grade Lymphoproliferative Disorders.

Abstract 5076 IntroductionOmega 3 fatty acids, when supplemented to cell culture or in the diet of tumor bearing animals, have been shown to sensitize mouse leukemias and lymphomas or multiple human solid tumor types to chemotherapy drugs. Enhanced chemosensitivity has been associated with suppression of nuclear factor kappa B (NFkB) activation and increased susceptibility to lipid peroxidation. Some investigators have expressed concerns over a possible bleeding diathesis related to the chronic consumption of these supplements. Patients and MethodsWe have initiated a pilot study in patients with low grade lymphoproliferative disorders to determine omega 3 fatty acids supplements tolerance; correlation of oral supplementation with incorporation of omega 3 fatty acids in blood cell membranes and in-vitro sensitivity of leukemia cells to chemotherapy. Omega 3 capsules, containing 1250 mg total oil, 60% of which is omega 3 were administered 3 times daily. Doses were escalated after the first month to 6 capsules per day and to 9 capsules after the second month, if there was good tolerance. As part of safety monitoring, platelet aggregation studies were done at base line and at 6 months, utilizing a Siemens Dade PFA-100 analyzer. Fatty acid composition of red blood cells was assessed using gas chromatography. ResultsEight patients with Chronic Lymphocytic Leukemia (Rai stage 0-1, no requiring therapy) have been accrued to date. Six of the 8 patients were also receiving aspirin at the time of study. A dose-related increase in the omega 3 fatty acid content of both red blood cells and leukocytes was documented. The total omega 3 content of red cells was about 80% over base line after 3 capsules per day for one month; after 6 capsules per day the total omega 3 content of erythrocytes was about 160% over baseline. The omega 3 content of leukocytes after supplementation was much more variable ranging from -0.5% to 280% over baseline after 3 capsules per day and 37% to 416% over baseline after 6 capsules per day. Baseline Collagen/ADP aggregation was within the normal range in all patients: mean 72.4 sec (range 59-110) (normal- 70-118), no significant changes were noted at 6 months: mean 69.2 sec (range: 59-85). Baseline Collagen/EPI aggregation was elevated in 2 patients (>300 sec), the remaining patients had normal values with a mean of 100.3 sec (normal range: 74-193). At 6 months, Collagen/EPI aggregation showed a mean value of 129.3 sec (range 110-158), representing a mean 29.6% increase over baseline. Omega3 fatty acid supplements were generally well tolerated. Currently, 6 patients are up to 6 capsules/day and 2 are at 9 capsules/day. Two patients had Grade I intermittent diarrhea (1 patient at 6 capsules/day); 1 patient noted hand bruising. ConclusionsClearly, humans can consume enough omega 3 supplements to elicit biological activity as shown by the increase in fatty acid content of erythrocytes and leukocytes. No changes in Collagen/ADP aggregation was noted after 6 months of supplementation. A mild increase in Collagen/EPI aggregation is reported, with values that remained within the normal range, even in patients also medicated with aspirin. Studies are in progress to determine effects on NFkB activity and lipid peroxidation. DisclosuresNo relevant conflicts of interest to declare.

Methylation‐associated silencing of SFRP1 with an 8p11‐12 amplification inhibits canonical and non‐canonical WNT pathways in breast cancers

Recently, we analysed the 8p11-12 genomic region for copy number and gene expression changes in a panel of human breast cancer cell lines and primary specimens. We found that SFRP1 (Secreted frizzled related protein 1) is frequently under expressed even in breast tumours with copy number increases in this genomic region. SFRP1 encodes a WNT signalling antagonist, and plays a role in the development of multiple solid tumour types. In this study, we analysed methylation-associated silencing of the SFRP1 gene in breast cancer cells with the 8p11-12 amplicon, and investigated the tumour suppressor properties of SFRP1 in breast cancer cells. SFRP1 expression was markedly reduced in both the breast cancer cell lines and primary tumour specimens relative to normal primary human mammary epithelial cells even when SFRP1 is amplified. Suppression of SFRP1 expression in breast cancer cells with an SFRP1 gene amplification is associated with SFRP1 promoter methylation. Furthermore, restoration of SFRP1 expression suppressed the growth of breast cancer cells in monolayer, and inhibited anchorage independent growth. We also examined the relationship between the silencing of SFRP1 gene and WNT signalling in breast cancer. Ectopic SFRP1 expression in breast cancer cells suppressed both canonical and non-canonical WNT signalling pathways, and SFRP1 expression was negatively associated with the expression of a subset of WNT responsive genes including RET and MSX2. Thus, down-regulation of SFRP1 can be triggered by epigenetic and/or genetic events and may contribute to the tumourigenesis of human breast cancer through both canonical and non-canonical WNT signalling pathways.

GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer.

Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in multiple solid tumor types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Integrative analysis of the region identifies a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to TOR signaling. Mechanistically, GOLPH3 regulates cell size, enhances growth factor-induced mTOR signaling in human cancer cells and alters response to mTOR inhibitor in vivo. Thus, reinforcing genomic and genetic, biological, functional and biochemical data in yeast and humans establish GOLPH3 as a novel oncogene that is commonly targeted for amplification in human cancer and capable of modulating the response to rapamycin, a cancer drug in clinical use.

Population pharmacokinetic (PK) analysis of ABT-869 in solid tumors and acute myelogenous leukemia (AML) patients

3567 Background: ABT-869 is an orally bioavailable, potent and specific inhibitor of all vascular endothelial growth factor and platelet derived growth factor family receptor tyrosine kinases. The objectives of this analysis were to understand the population pharmacokinetics of ABT-869 and explore the effect of several demographic/disease state covariates influencing ABT-869 disposition. Methods: A population PK analysis of 181 patients (pts) enrolled in two phase 1 (multiple types of solid tumors and AML) and three phase 2 monotherapy studies (non-small cell lung cancer, hepatocellular carcinoma [HCC] and renal cell carcinoma) was conducted. Approximately 90% of pts received ABT-869 based on body-weight dosing while the remaining pts had flat dosing. Available plasma concentrations obtained after intensive and sparse pre-dose PK sampling were analyzed by population PK using the non linear mixed effects modeling (NONMEM) approach. Potential covariates including body weight, body surface area (BSA), age, sex, creatinine clearance (CrCL) and disease state (HCC vs. non-HCC pts) were tested. Results: The mean body weight of enrolled pts was 71 kg and 57% were Asian, 36% Caucasian and 7% other races. The ABT-869 plasma concentration time profile was well described by a one-compartment model with first order absorption and elimination process. Oral clearance (CL/F) was not affected by body weight (range 35–177 kg); however, apparent volume of distribution (V/F) increased by 6L per 0.1 mg/m2 increase in BSA. CrCL (39.9–290.3 ml/min) was not a significant covariate on V/F and CL/F suggesting renally impaired pts do not require a different dose/dosing regimen. HCC pts had ∼40% lower CL/F values than pts with other malignancies suggesting a lower dose would be appropriate for HCC (Child Pugh A and B) pts. Conclusions: Population PK analysis showed that ABT-869 PK can be well described by a one-compartment model with first order absorption and elimination. Race and impaired renal function does not appear to alter PK. HCC pts had lower CL/F value therefore a lower dose may be recommended in these patients. Implications of increased V/F with increasing body size and appropriate dosing strategy are undergoing further analysis. [Table: see text]

A Selective Phosphatase of Regenerating Liver Phosphatase Inhibitor Suppresses Tumor Cell Anchorage-Independent Growth by a Novel Mechanism Involving p130Cas Cleavage

The phosphatase of regenerating liver (PRL) family, a unique class of oncogenic phosphatases, consists of three members: PRL-1, PRL-2, and PRL-3. Aberrant overexpression of PRL-3 has been found in multiple solid tumor types. Ectopic expression of PRLs in cells induces transformation, increases mobility and invasiveness, and forms experimental metastases in mice. We have now shown that small interfering RNA-mediated depletion of PRL expression in cancer cells results in the down-regulation of p130Cas phosphorylation and expression and prevents tumor cell anchorage-independent growth in soft agar. We have also identified a small molecule, 7-amino-2-phenyl-5H-thieno[3,2-c]pyridin-4-one (thienopyridone), which potently and selectively inhibits all three PRLs but not other phosphatases in vitro. The thienopyridone showed significant inhibition of tumor cell anchorage-independent growth in soft agar, induction of the p130Cas cleavage, and anoikis, a type of apoptosis that can be induced by anticancer agents via disruption of cell-matrix interaction. Unlike etoposide, thienopyridone-induced p130Cas cleavage and apoptosis were not associated with increased levels of p53 and phospho-p53 (Ser(15)), a hallmark of genotoxic drug-induced p53 pathway activation. This is the first report of a potent selective PRL inhibitor that suppresses tumor cell three-dimensional growth by a novel mechanism involving p130Cas cleavage. This study reveals a new insight into the role of PRL-3 in priming tumor progression and shows that PRL may represent an attractive target for therapeutic intervention in cancer.

Vascular endothelial growth factor and bevacitumab in breast cancer

Cancer development requires neovascularization. The level of angiogenic activity in breast cancer has been shown to be a determinant of disease progression and survival. Vascular endothelial growth factor (VEGF) is a one of the most essential pro-angiogenic growth factors expressed by most cancer-cell types and certain tumor stromal cells. Blocking the action of VEGF appears to be a promising anti-angiogenic approach to treat multiple types of solid tumors including breast cancer, and clinical trials using agents which target VEGF were launched beginning in the late 1990s. The effort reached fruition in 2005 with the first report of a large, prospective randomized trial of anti-VEGF therapy in patients with metastatic breast cancer (MBC), which demonstrated the benefit of adding the monoclonal antibody bevacizumab to the chemotherapeutic agent paclitaxel. The success of this trial provided proof of principle that inhibition of angiogenesis has the potential to enhance the effectiveness of treatment of this disease. Adjuvant therapy trials are in development with bevacizumab and numerous other anti-VEGF agents are now being tested in patients with breast cancer in various settings. Nevertheless, since bevacizumab monotherapy has minimal activity, a question for future therapeutic development of these agents in breast cancer relates to the interaction between anti-angiogenic strategies and cytotoxic therapies. Further research is still needed for complete understanding of the exact role of VEGF and angiogenesis in health and disease, to take best advantage and avoid the adverse effects of anti-angiogenic therapy.

Vascular Targeted Therapy With Anti–Prostate-Specific Membrane Antigen Monoclonal Antibody J591 in Advanced Solid Tumors

Based on prostate-specific membrane antigen (PSMA) expression on the vasculature of solid tumors, we performed a phase I trial of antibody J591, targeting the extracellular domain of PSMA, in patients with advanced solid tumor malignancies. This was a proof-of-principle evaluation of PSMA as a potential neovascular target. The primary end points were targeting,toxicity, maximum-tolerated dose, pharmacokinetics (PK), and human antihuman antibody (HAHA) response. Patients had advanced solid tumors previously shown to express PSMA on the neovasculature. They received 111Indium (111ln)-J591 for scintigraphy and PK, followed 2 weeks later by J591 with a reduced amount of 111In for additional PK measurements. J591 dose levels were 5, 10, 20, 40, and 80 mg. The protocol was amended for six weekly administrations of unchelated J591. Patients with a response or stable disease were eligible for re-treatment. Immunohistochemistry assessed PSMA expression in tumor tissues. Twenty-seven patients received monoclonal antibody (mAb) J591. Treatment was well tolerated. Twenty (74%) of 27 patients had at least one area of known metastatic disease targeted by 111In-J591, with positive imaging seen in patients with kidney, bladder, lung, breast, colorectal, and pancreatic cancers, and melanoma. Seven of 10 patient specimens available for immunohistochemical assessment of PSMA expression in tumor-associated vasculature demonstrated PSMA staining. No HAHA response was seen. Three patients of 27 with stable disease received re-treatment. Acceptable toxicity and excellent targeting of known sites of metastases were demonstrated in patients with multiple solid tumor types, highlighting a potential role for the anti-PSMA antibody J591 as a vascular-targeting agent.

Epithelial to Mesenchymal Transition Is a Determinant of Sensitivity of Non–Small-Cell Lung Carcinoma Cell Lines and Xenografts to Epidermal Growth Factor Receptor Inhibition

Treatment of second- and third-line patients with non-small-cell lung carcinoma (NSCLC) with the epidermal growth factor receptor (EGFR) kinase inhibitor erlotinib significantly increased survival relative to placebo. Whereas patient tumors with EGFR mutations have shown responses to EGFR inhibitors, an exclusive role for mutations in patient survival benefit from EGFR inhibition is unclear. Here we show that wild-type EGFR-containing human NSCLC lines grown both in culture and as xenografts show a range of sensitivities to EGFR inhibition dependent on the degree to which they have undergone an epithelial to mesenchymal transition (EMT). NSCLC lines which express the epithelial cell junction protein E-cadherin showed greater sensitivity to EGFR inhibition in vitro and in xenografts. In contrast, NSCLC lines having undergone EMT, expressing vimentin and/or fibronectin, were insensitive to the growth inhibitory effects of EGFR kinase inhibition in vitro and in xenografts. The differential sensitivity of NSCLC cells with epithelial or mesenchymal phenotypes to EGFR inhibition did not correlate with cell cycle status in vitro or with xenograft growth rates in vivo, or with total EGFR protein levels. Cells sensitive to EGFR inhibition, with an epithelial cell phenotype, did exhibit increased phosphorylation of EGFR and ErbB3 and a marked increase in total ErbB3. The loss of E-cadherin and deregulation of beta-catenin associated with EMT have been shown to correlate with poor prognosis in multiple solid tumor types. These data suggest that EMT may be a general biological switch rendering non-small cell lung tumors sensitive or insensitive to EGFR inhibition.

Formulating Paclitaxel in Nanoparticles Alters Its Disposition

Paclitaxel is active and widely used to treat multiple types of solid tumors. The commercially available paclitaxel formulation uses Cremophor/ethanol (C/E) as the solubilizers. Other formulations including nanoparticles have been introduced. This study evaluated the effects of nanoparticle formulation of paclitaxel on its tissue distribution. We compared the plasma and tissue pharmacokinetics of paclitaxel-loaded gelatin nanoparticles and the C/E formulation. Mice were given paclitaxel-equivalent doses of 10 mg/kg by intravenous injection. The nanoparticle and C/E formulations showed significant differences in paclitaxel disposition; the nanoparticles yielded 40% smaller area under the blood concentration-time curve and faster blood clearance of total paclitaxel concentrations (sum of free, protein-bound, and nanoparticle-entrapped drug). The two formulations also showed different tissue specificity. The rank order of tissue-to-blood concentration ratios was liver > small intestine > kidney >> large intestine > spleen = stomach > lung > heart for the nanoparticles, and liver > small intestine > large intestine > stomach > lung > or = kidney > spleen > heart for the C/E formulation. The nanoparticles also showed longer retention and higher accumulation in organs and tissues (average of 3.2 +/- 2.3-fold), especially in the liver, small intestine, and kidney. The most striking difference was an 8-fold greater drug accumulation and sustained retention in the kidney. These data indicate that formulation of paclitaxel affects its clearance and distribution into tissues, with preferential accumulation of nanoparticles in the liver, spleen, small intestine, and kidney.