Antitumor Efficacy Of Paclitaxel Research Articles

Paclitaxel-lipid prodrug liposomes for improved drug delivery and breast carcinoma therapy

Paclitaxel (PTX) is widely applied for the treatment of unresectable and metastasis breast carcinoma as well as other cancers, whereas its efficacy is always impeded by poor solubility. Liposomes are one kind of the most successful drug carriers which are capable of solubilizing PTX and improving patients’ tolerance owing to excellent biocompatibility and biodegradability. However, poor compatibility between PTX and liposomes compromises the stability, drug loading and anti-tumor capacity of liposomal formulations. To address this issue, three lipids with various chain lengths, namely, myristic acid (MA, 14C), palmitic acid (PA, 16C) and stearic acid (SA, 18C), were conjugated to PTX via ester bonds and the synthesized prodrugs with high lipophilicity were further formulated into liposomes, respectively. All liposomes show high stability and drug loadings, as well as sustained drug release. The chain lengths of lipids are negatively correlated with drug release and enzymatic conversion rates, which further impact the pharmacokinetics, tumor accumulation, and anti-tumor efficacy of liposomal PTX. Neither rapid nor slow drug release facilitates high tumor accumulation as well as anti-tumor efficacy of PTX. Among all liposomes, PTX-PA-loaded liposomes show the longest circulation and highest tumor accumulation of PTX and exert the most potent anti-tumor capacities in vivo, owing to its moderate drug release and enzymatic conversion rate. Witnessing its superior safety, PTX-PA liposomes hold potential for further clinical translation.

The Potential Usefulness of 99mTc-HYNIC-(Ser)3-LTVPWY Peptide for Predicting HER2 Status Alteration After Chemotherapy in Ovarian Tumor-Bearing Mice.

Purpose: The assessment of HER2 expression has a significant impact on optimizing cancer treatment protocol in patients. The aim of this study was to evaluate the potential usefulness of 99mTc-HYNIC-(Ser)3-LTVPWY peptide for detecting HER2 alteration after paclitaxel therapy of ovarian tumor xenografts in nude mice. Materials and Methods: Mice bearing SKOV-3 tumors were treated with paclitaxel and saline. The antitumor efficacy of paclitaxel was compared with the control group in tumor size and histopathological examinations. In biodistribution and imaging studies, the tumor uptakes of radiolabeled peptide were evaluated in mice-bearing ovarian tumors in both groups. The HER2 expressions in transplanted tumors were analyzed by immunohistochemistry (IHC). Results: Tumor size gradually increased in all mice during the treatment, whereas tumors had considerably faster growth in the saline group compared to those in the paclitaxel-treated mice. Paclitaxel could suppress ovarian tumor growth and prevent vascular and cell proliferation in the tumoral mass. Biodistribution and imaging results demonstrated nonsignificant radionuclide accumulations in transplanted tumors in the paclitaxel- and saline-treated groups. IHC staining confirmed the HER2 status that was similar in both groups. Conclusions: The response of HER2 status to paclitaxel in mice bearing HER2-expression tumors was profitably monitored by HER2 targeted 99mTc-HYNIC-(Ser)3-LTVPWY peptide that was agreement with IHC. The utilization of this radiolabeled peptide may be a valuable probe in evaluating HER2 status after chemotherapy.

Protamine and BSA–dextran complex emulsion improves oral bioavailability and anti-tumor efficacy of paclitaxel

Food protein and polysaccharide complex emulsions are safe carriers of hydrophobic drugs and nutrients. To improve oral bioavailability and therapeutic/healthy efficacy of hydrophobic drugs and nutrients, herein, protamine (PRO), a cationic cell-penetrating peptide, was introduced into protein and polysaccharide complex emulsion. The electrostatic complex of PRO and BSA–dextran conjugate (BD) produced by Maillard reaction was used as emulsifier to produce oil-in-water emulsion (@BD/PRO). The BSA molecules were crosslinked at the oil–water interface by a heat treatment and the PRO chains were simultaneously anchored in the interface. BD emulsion (@BD) without PRO was produced for comparation. Paclitaxel (PTX), a hydrophobic antineoplastic drug, was encapsulated in the emulsions with 99% loading efficiency and 6.4% loading capacity. The emulsions had long-term stability. The bioavailability and H22 tumor inhibition efficacy of PTX@BD/PRO were 40% and 70% higher than those of PTX@BD, respectively, after oral administration in the mice. More importantly, orally administrated PTX@BD/PRO had the same anti-tumor efficacy as intravenously injected commercial PTX injection. No abnormality was observed in the main organs of the mice after consecutive oral administration of PTX@BD/PRO. This study indicates that @BD/PRO is an excellent carrier of hydrophobic drugs/nutrients and is suitable for long-term oral administration.

HM30181A, a potent P-glycoprotein inhibitor, potentiates the absorption and in vivo antitumor efficacy of paclitaxel in an orthotopic brain tumor model.

Objective:Delivery of chemotherapeutic drugs to the brain has remained a major obstacle in the treatment of glioma, owing to the presence of the blood-brain barrier and the activity of P-gp, which pumps its substrate back into the systemic circulation. The aim of the present study was to develop an intravenous formulation of HM30181A (HM) to inhibit P-gp in the brain to effectively deliver paclitaxel (PTX) for the treatment of malignant glioma.Methods:Two formulations of solubilized HM were designed on the basis of different solid dispersion strategies: i) spray-drying [polyvinlypyrrolidone (PVP)-HM] and ii) solvent evaporation [HP-β-cyclodextrin (cyclodextrin)-HM]. The P-gp inhibition of these 2 formulations was assessed on the basis of rhodamine 123 uptake in cancer cells. Blood and brain pharmacokinetic parameters were also determined, and the antitumor effect of cyclodextrin-HM with PTX was evaluated in an orthotopic glioma xenograft mouse model.Results:Although both PVP-HM and cyclodextrin-HM formulations showed promising P-gp inhibition activity in vitro, cyclodextrin-HM had a higher maximum tolerated dose in mice than did PVP-HM. Pharmacokinetic study of cyclodextrin-HM revealed a plasma concentration plateau at 20 mg/kg, and the mice began to lose weight at doses above this level. Cyclodextrin-HM (10 mg/kg) administered with PTX at 10 mg/kg showed optimal antitumor activity in a mouse model, according to both tumor volume measurement and survival time (P < 0.05).Conclusions:In a mouse orthotopic brain tumor model, the intravenous co-administration of cyclodextrin-HM with PTX showed potent antitumor effects and therefore may have potential for glioma therapy in humans.

Abstract P6-21-04: Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss

Abstract Background: PTEN functions as a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway to promote balanced cell proliferation, survival and differentiation. PTEN loss occurs across a variety of cancer subtypes; PTEN-deficient tumors are dependent on PI3Kβ activity, making PI3Kβ a compelling target. We evaluated the efficacy of PI3Kβ inhibitor AZD8186 as a single agent and in combination with standard chemotherapy and immune checkpoint inhibitors focused on tumors with loss of PTEN function. Methods: In vitro, cell proliferation assays were performed to determine the half maximal inhibitory concentration (IC50) after 3 days of treatment and to test the effects in combination with standard chemotherapy. Colony formation assays were performed to confirm efficacy of AZD8186 in PTEN-deficient cell lines. Western blot analysis was performed to assess PTEN protein expression and to evaluate effects of AZD8186 on PI3K signaling. In vivo, antitumor efficacy of AZD8186 as a single agent as well as in combination with paclitaxel and anti-PD1 was evaluated. Results: AZD8186 inhibited the cell proliferation of three of ten TNBC cell lines in vitro; PTEN loss was significantly correlated with AZD8186 sensitivity (p= 0.008). Colony formation assay confirmed sensitivity of PTEN-deficient cell lines to AZD8186. AZD8186 inhibited PI3K signaling with decreased expression of pAKT, pGSK3β, pPRAS40 and pS6. AZD8186 treatment of PTEN-deficient cell lines, MDA-MB-436 and MDA-MB-468, resulted in increased apoptosis. Cell proliferation assays demonstrated additive effect of the combination of paclitaxel with AZD8186. AZD8186 significantly enhanced antitumor activity of paclitaxel in MDA-MB-436 and MDA-MB-468 cell-line-derived xenografts, with disease stabilization in the latter. In syngeneic models, AZD8186 enhanced antitumor efficacy of anti-PD1 antibodies in PTEN-deficient BP murine melanoma xenograft (p=0.0073), but not in PTEN-wildtype colon carcinoma, CT26. Conclusion: AZD8186 has single agent efficacy in PTEN-deficient triple negative breast cancer cell lines in vitro, with modest single agent efficacy in vivo. AZD8186 enhanced the antitumor efficacy of paclitaxel and of Anti-PD1 antibodies in vivo. Further study is needed to determine optimal combination therapies for PTEN-deficient solid tumors. Citation Format: Owusu-Brackett N, Zhao M, Akcakanat A, Evans KW, Yuca E, Tapia C, Ileana-Dumbrava E, Janku F, Meric-Bernstam F. Targeting PI3Kβ alone and in combination with chemotherapy or immunotherapy in tumors with PTEN loss [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-21-04.

Abstract P6-20-11: The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, enhances antitumor efficacy of paclitaxel and Nab-paclitaxel in TP53 wild-type MCF-7 breast cancer models

Abstract Background: MDMX and MDM2 are endogenous inhibitors of the p53 tumor suppressor protein. MDMX levels are frequently elevated in luminal breast cancer, which generally expresses wild-type p53. ALRN-6924, an α-helical stapled peptide, is the first and only dual inhibitor of MDMX and MDM2 currently in clinical trials for solid tumors and hematological malignancies. We sought to determine the antitumor efficacy of the combination of ALRN-6924 with taxanes in models of human breast cancer. Methods: Sulforhodamine B colorimetric assay was used to assess the cytotoxicity of the combination of ALRN-6924 with taxanes in vitro. Athymic nude mice were implanted with MCF-7 tumors and treated for four weeks with ALRN-6924 alone and in combination with paclitaxel in cremaphor (Taxol®, study #1) or a nanoparticle-albumin-bound (nab) formulation (Abraxane®, study #2). In study #1, ALRN-6924 (5, 10 mg/kg) was dosed twice weekly and paclitaxel (10, 15 mg/kg) was dosed weekly, with paclitaxel administered 6 h prior to ALRN-6924. In study #2, ALRN-6924 alone (5 mg/kg) was dosed twice weekly while nab-paclitaxel (15 mg/kg) was administered weekly in combination at -24h, -6h, 0h, +6h, or +24h relative to ALRN-6924 administration. Results: ALRN-6924 was found to have synergistic activity with paclitaxel in both MCF-7 and ZR-75-1 cell lines in vitro (Combination index: 0.874 and 0.323 respectively). In in vivo study #1, the combination of ALRN-6924 and paclitaxel significantly inhibited MCF-7 tumor growth compared to either agent alone (p&amp;lt;0.005). Paclitaxel 15 mg/kg + ALRN-6924 5 mg/kg resulted in the greatest tumor inhibition with average tumor size decreased by 13% at four weeks versus the starting size. In study #2, the combination of nab-paclitaxel with ALRN-6924 administered -6h to +24h relative to nab-paclitaxel resulted in improved efficacy over either single agent and a significant increase in the number of tumor regressions (up to 6/10 with 3 consecutive measurements &amp;lt;50% of starting volume) compared to nab-paclitaxel alone (1/10, p&amp;lt;0.005). When ALRN-6924 was administered 24h prior to nab-paclitaxel, there was a marked decrease in efficacy and no tumor regressions were observed. In both studies, drug treatments were well tolerated with no significant weight loss in mice. Conclusion: The significant increase in efficacy observed with ALRN-6924 in combination with paclitaxel supports further evaluation in patients with breast cancer. Citation Format: Pairawan SS, Yuca E, Evans K, Annis A, Narasimhan N, Sutton D, Carvajal LA, Ren J-G, Santiago S, Guerlavais V, Akcakanat A, Tapia C, Illeana Dumbrava EE, Aivado M, Meric-Bernstam F. The stapled peptide ALRN-6924, a dual inhibitor of MDMX and MDM2, enhances antitumor efficacy of paclitaxel and Nab-paclitaxel in TP53 wild-type MCF-7 breast cancer models [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-11.

Antitumor Efficacy of Paclitaxel-Loaded Polylactide/Poly(ethylene glycol) Nanoparticles Combination with Exercise in Tumor-Bearing Mice

The nanoparticles (NPs) provide a promising prospect for tumor therapy, and exercise is also becoming readily and accepted as a beneficial adjunct therapy to maintain or enhance quality of life in cancer patients. We investigate the antitumor efficacy of paclitaxel (PT) loaded polylactide/poly(ethylene glycol) NPs (PT-PLA/PEG NPs) under the exercise conditions. Results showed that within the first 7 days, the PT concentration in tumor maintained at a higher level in the PT-PLA/PEG NPs + exercise (PT-PLA/PEG NPs + EX) group as compared with the PT-PLA/PEG NPs group. All the phagocytosis rates of macrophages were significantly decreased below the CON in exercise group. The most significant antitumor effect was observed in PT-PLA/PEG NPs + EX group, demonstrating that the PT-PLA/PEG NPs improved the concentration of PT, and exercise could further increased its therapeutic efficiency for tumor. These researches may provide an effective means for tumor therapy.

Abstract 601: Macitentan (ACT-064992), a tissue-targeting endothelin receptor antagonist enhances therapeutic efficacy of paclitaxel by modulating survival pathways in orthotopic models of metastatic human ovarian cancer

Abstract Introduction: In 2009, ovarian cancer was the leading cause of death from gynecologic cancer in the United States. Efforts to develop tools for early detection and therapeutic regimens to overcome drug resistance of the ovarian cancer have not made a significant achievement to prolong the median survial of the patients. Potential treatments for ovarian cancers that have become resistant to standard chemotherapies include modulators of tumor cell survival, such as endothelin receptor (ETR) antagonist. We investigated the therapeutic efficacy of the dual ETR antagonist, macitentan, on human ovarian cancer cells, SKOV3ip1 and IGROV1, growing orthotopically in nude mice. Materials and Methods: Mice were injected with one million cells of SKOV3ip1 or IGROV1. Ten days later, mice with established disease were randomized into vehicle (control), paclitaxel (weekly, intraperitoneal injections), macitentan (daily oral administrations) or a combination of paclitaxel and macitentan treatment groups. After 4 weeks of treatment, mice were necropsied and tumor incidence, tumor weight, and incidence of ascites were recorded. Tumor tissues were processed for immunohistochemical analyses. Results: Treatment with paclitaxel decreased tumor weight and volume of ascites. Combination therapy with macitentan and paclitaxel reduced tumor incidence and further reduced tumor weight and volume of ascites when compared with paclitaxel alone. Macitentan alone occasionally reduced tumor weight but alone had no effect on tumor incidence or ascites. Immunohistochemical analyses revealed that treatment with macitentan and macitentan plus paclitaxel inhibited the phosphorylation of ETRs and suppressed the survival pathways of tumor cells by decreasing the levels of pVEGFR2, pAkt, and pMAPK. The dose of macitentan necessary for inhibition of phosphorylation correlated with the dose required to increase antitumor efficacy of paclitaxel. Conclusion: Treatment with macitentan enhanced the cytotoxicity mediated by paclitaxel as measured by the degree of apoptosis in tumor cells and tumor-associated endothelial cells. Collectively, these results show that administration of macitentan in combination with paclitaxel prevents the progression of ovarian cancer in the peritoneal cavity of nude mice in part by inhibiting survival pathways of both tumor cells and tumor-associated endothelial cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 601. doi:10.1158/1538-7445.AM2011-601

Abstract P1-02-07: Real-Time Functional Imaging of Tumor Vascular Normalization by Anti-Angiogenic Agents

Abstract Background: We describe here new technology that enables non-invasive imaging of normalization of tumor blood vessels by anti-angiogenic agents in real time. Materials and Methods: Variable-magnification in vivo-fluorescence imaging as well as fluorescence tomography were used to visualize vessel normalization. Results: Morphological changes in the same vessel prior to and after drug treatment were imaged with high resolution in real time. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were functionally imaged. Tumor vessel normalization was demonstrated by significantly reduced leakiness and subsequent improved tumor delivery of Paclitaxel-BODPY as well as by normalized morphology. The tumor vascular pool agent, AngioSense750, was retained in tumors after both anti-VEGF antibody and rapamycin treatment as visualized by noninvasive fluorescence tomography. The anti-angiogenic therapy normalized vessels, which significantly enhanced the antitumor efficacy of Paclitaxel due to increased drug penetration throughout the tumor. Discussion: The optical imaging technology described here is thus a powerful real-tool imaging tool of functional and morphological tumor vessel normalization and its therapeutic consequences. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-02-07.

Diverse effects of docetaxel on inducible nitric oxide production in alveolar macrophages

Docetaxel is a derivative of paclitaxel (taxol), a diterpine plant compound that was isolated initially from the bark of the western yew tree, Taxus brevifolia, and is currently used as a fundamental drug in the treatment of a variety of solid cancers. The anti-tumor efficacy of paclitaxel has been attributed in part to modulatory effects on the generation of inflammatory mediators, in particular NO, in macrophages and tumor cells. The purpose of this study was to investigate the effects of docetaxel on lipopolysaccharide (LPS)-induced nitric oxide (NO) synthesis in alveolar macrophages isolated from rats. LPS-induced NO production and inducible NO synthase (iNOS) expression were significantly enhanced in the macrophages isolated from rats injected intraperitoneally with docetaxel (4mg/kg body weight per day for 5 consecutive days) compared with those in macrophages from control rats (vehicle administration). In vivo administration of docetaxel augmented LPS-induced p38 activation but not extracellular signal-related kinase (ERK) activation in isolated macrophages. By contrast, in vitro treatment of macrophages with docetaxel (5 and 10 microg/ml) inhibited LPS-induced NO production and iNOS expression. Thus, in vitro effects of docetaxel on NO generation of macrophages do not explain its in vivo effects. Release of lactate dehydrogenase (LDH) from macrophages was neither affected by in vitro treatment with docetaxel (up to 10 microg/ml) nor by its in vivo administration. These results suggest that docetaxel exerts diverse actions on LPS-induced iNOS expression in alveolar macrophages. We suggest that the in vivo action of docetaxel is mediated by stimulation of p38 activity.

Assessment of resistance to paclitaxel of murine tumors by 99mTc-MIBI/ 201Tl dual-radionuclide imaging

This study investigated P-glycoprotein (Pgp) expression by murine tumors with and without resistance to paclitaxel and the role of 99mTc-2-methoxyisobutylisonitrile (MIBI)/ 201Tl imaging in predicting the effect of paclitaxel. Antitumor effect of paclitaxel and biodistribution of the radiopharmaceuticals were evaluated in mice bearing four tumor types. Pgp expression did not correlate with the antitumor efficacy of paclitaxel. Although the absolute uptake of 99mTc-MIBI did not correlate with Pgp expression, 99mTc-MIBI could predict paclitaxel sensitivity by its higher uptake.

Comparative antitumor efficacy of docetaxel and paclitaxel in nude mice bearing human tumor xenografts that overexpress the multidrug resistance protein (MRP)

Multidrug resistance has been associated with expression of the multidrug resistance protein (MRP). Recently, MRP-expression has been detected in human tumor samples of patients with breast cancer and non-small-cell lung cancer. Since taxoids are the most active drugs in the treatment of both tumor entities, the antitumor efficacies of paclitaxel and docetaxel were compared in nude mice bearing human tumor xenografts that express MRP. Athymic nude mice (nu/nu) bearing tumor xenografts of parental human sarcoma HT1080 or MRP-expressing HT1080/DR4 cells (as confirmed by Northern blot analysis) were treated with the maximum tolerated doses (MTD) of doxorubicin ([Dx] 10 mg/kg i.v. push), paclitaxel ([PC] 50 mg/kg three-hour i.v. infusion), or docetaxel ([DC] 40 mg/kg three-hour i.v. infusion). In vitro, the activity of doxorubicin, paclitaxel and docetaxel was evaluated by the sulphorhodamine B (SRB) assay using the pyridine analogue PAK-104P (5 microM), a potent inhibitor of MRP-function. At their MTDs both taxoids showed significant activity against MRP-negative HT1080 xenografts with response rates of 80% (40% CR) for PC and 100% (60% CR) for DC. In contrast, DC was significantly more active than PC in nude mice bearing doxorubicin resistant MRP-expressing HT1080/DR4 tumor xenografts (overall response rates: 100% (60% CR) for DC; 10% (0% CR) for PC; 0% for Dx). Since treatment of mice with the MTD of PC or DC yielded similar overall toxicity (maximum weight loss for HT1080: PC 8.6 +/- 2.2%; DC 7.5 +/- 2.2% and for HT1080/DR4: PC 11.6 +/- 3.0%; DC 7.6 +/- 1.8%, respectively), these results demonstrate the increase in the therapeutic index for docetaxel against MRP-expressing tumors. In vitro, HT1080/DR4 cells were 270-fold, 6.4-fold and 2.8-fold more resistant than parental cells to doxorubicin, PC and DC, respectively. Pyridine analogue PAK-104P completely restored drug sensitivity to PC and DC, while no effect of PAK-104P on parental HT1080 cells was observed. Both taxoids, when given at their MTDs, showed significant efficacy against parental HT1080 tumor xenografts. However, docetaxel at its MTD was significantly more active against MRP-expressing tumor xenografts than paclitaxel. Furthermore, in vitro resistance of HT1080/DR4 cells was higher for PC (6.4-fold) than for DC (2.8-fold). Since PAK-104P completely restored sensitivity to both taxoids, the observed resistance appears to be related to MRP. These data suggest, that docetaxel is not as readily transported by MRP as paclitaxel leading to an increased therapeutic ratio in MRP-expressing tumors in vivo. Therefore, docetaxel may have therapeutic advantages in the clinical treatment of MRP-expressing tumors.