Panel Of Human Tumor Xenografts Research Articles

Abstract 1657: Evaluating anti-tumor activity of the human anti-PD-1 antibody pembrolizumab using humanized mouse models

Abstract Targeting immune checkpoints has proven to be an effective strategy for reactivating the immune system to elicit potent anti-tumor activity. For example, the anti-PD-1 antibody pembrolizumab has shown robust and durable clinical activity in numerous malignancies including melanoma and non-small cell lung cancer. Unfortunately, a subset of patients do not benefit from pembrolizumab treatment. Ongoing molecular analyses of patient samples are establishing gene signatures which aim to more accurately predict which patients will benefit from immunotherapy. However, there are currently no preclinical in vivo platforms that comprehensively translate these clinical findings. Therefore, we have explored the use of mice engineered with a human immune system to examine the anti-tumor activity of pembrolizumab against a panel of human tumor xenografts derived from both cultured cell lines as well as patient tissue. Tumor models were selected based on parameters including PD-L1 expression and mutational load in order to closely mimic responder patients in the ongoing pembrolizumab clinical trials. Our data confirm that pembrolizumab can induce significant anti-tumor efficacy in humanized mice inoculated with human tumor models derived from both cancer cell lines and patient tumors. In responsive models, pembrolizumab caused significant tumor growth inhibition and, in some instances, tumor regressions. FACS analyses confirmed effective targeting of PD-1+ T cell populations. Anti-tumor efficacy correlated with increased effector T cell to regulatory T cell ratios as well as an elevated T cell infiltrate presence. Nonresponsive models lacked robust immune infiltration detectable by FACS or IHC, consistent with clinical data. Furthermore, presence of cytolytic activity at baseline and T-cell inflamed environment were evaluated using transcriptome analysis and subsequently linked to pembrolizumab response and to somatic neoantigen burden of the tumors. Together these studies validate the utility of humanized mice in the preclinical development of novel cancer immunotherapies and may also be beneficial in better defining the patient responder hypothesis and its prognostic value. Additionally, humanized mice may help identify optimal combination treatment regimens to provide more meaningful clinical benefit to patients who do not respond to single-agent therapy with pembrolizumab. Citation Format: Douglas E. Linn, Razvan Cristescu, Kallol Ray, Shuli Zhang, Sripriya Dhandapani, Sarav Kaliyaperumal, Jennifer H. Yearley, Brian J. Long. Evaluating anti-tumor activity of the human anti-PD-1 antibody pembrolizumab using humanized mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1657. doi:10.1158/1538-7445.AM2017-1657

Abstract C197: Accurins improve the pharmacokinetics, pharmacodynamics, tolerability and anti-tumor activity of the AKT inhibitor MK-2206

Abstract Background: BIND-2206 Accurins are novel polymeric nanoparticles encapsulating MK-2206, a Merck AKT inhibitor in phase 2 trials. MK-2206 targets the phosphatidylinositol 3-kinase (PI3K) pathway via AKT inhibition and has demonstrated therapeutic efficacy in the treatment of cancer albeit with dose limiting toxicities. Accurins have shown promise for targeting oncology agents preferentially to tumors, while limiting systemic exposure. To determine if encapsulation of MK-2206 improves therapeutic index, studies were performed to evaluate pharmacokinetics (PK), pharmacodynamics (PD), tolerability and anti-tumor activity compared to parent MK-2206. Materials and Methods: PK of four Accurin formulations with varying in vitro drug release rates was evaluated. Based on these data, two lead Accurins (BIND-2206C and BIND-2206D) were selected for further characterization. Since AKT inhibitors are documented to induce hyperglycemia in mice, blood glucose levels were also evaluated after acute administration of BIND-2206 Accurins or parent MK-2206 as a measure of tolerability. Using a panel of human tumor xenografts (VCaP, SK-OV-3 and BT-474) anti-tumor activity of the Accurins was assessed in mice. When tumors were established mice were dosed orally with parent MK-2206 or intravenously with BIND-2206 Accurins two or three times per week on a three week cycle. Tumor volume was measured post treatment to determine anti-tumor activity. Following final drug administration, tumors were collected for PK and PD evaluation. Extent and duration of tumor target inhibition was evaluated by measuring pAKT and total AKT using a mesoscale discovery method and was correlated to tumor MK-2206 levels. Results: Accurins BIND-2206C and BIND-2206D significantly enhanced the PK profile of parent MK-2206 by increasing Cmax (33 fold) and AUC (222 fold) and decreasing clearance (38 fold) in mice. In addition, both BIND-2206 Accurins improved tolerability as demonstrated by no hyperglycemic response compared to a 300% increase in blood glucose in nude mice treated with parent MK-2206. In the VCaP human prostate cancer tumor model, BIND-2206C inhibited tumor growth by 88% and BIND-2206D induced 16% tumor regression showing significant enhancement of anti-tumor efficacy compared to 55% tumor growth inhibition achieved by parent MK-2206. This correlated with high tumor exposure at 72 hours and prolonged tumor PD at 96 hours post dose for both Accurins compared to parent MK-2206. A similar increase in tumor exposure and prolonged PD response resulted in enhanced anti-tumor efficacy for BIND-2206 Accurins in the SK-OV-3 human ovarian cancer tumor model. In the BT-474 HER2 over-expressing human breast cancer tumor model, BIND-2206 Accurins did not improve efficacy compared to parent drug, although there was significant and prolonged tumor PD correlating with enhanced tumor PK. This suggests that anti-tumor efficacy is model specific and a combination strategy in the BT-474 model may be advantageous. Conclusions: BIND-2206 Accurins showed differentiated PK, increased tumor exposure, prolonged duration of target inhibition, superior efficacy and enhanced tolerability compared to parent MK-2206. These data suggest that nanoparticle formulations of the AKT inhibitor, MK-2206, may provide improved tolerability and therapeutic efficacy in a clinical setting. Citation Format: Louise Cadzow, Michael H. Lam, Young Ho Song, Maria Figueiredo, Hong Wang, David De Witt, Vincenzo Pucci, Jan-Rung Mo, Eric Lewis-Clark, Heidi Ferguson, Marian Gindy, Susan Low, Steve Zale, Jeff Hrkach, Caroline McGregor, Brian J. Long. Accurins improve the pharmacokinetics, pharmacodynamics, tolerability and anti-tumor activity of the AKT inhibitor MK-2206. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C197.

A multifunctional drug combination shows highly potent therapeutic efficacy against human cancer xenografts in athymic mice.

The tumor microenvironment plays a crucial role during tumor development. Integrated combination of drugs that target tumor microenvironment is a promising approach to anticancer therapy. Here, we report a multifunctional combination of low-cytotoxic drugs composed of dipyridamole, bestatin and dexamethasone (DBDx) which mainly acts on the tumor microenvironment shows highly potent antitumor efficacy in vivo. In mouse hepatoma H22 model, the triple drug combination showed synergistic and highly potent antitumor efficacy. The combination indices of various combinations of the triple drugs were between 0.2 and 0.5. DBDx inhibited the growth of a panel of human tumor xenografts and showed no obvious systemic toxicity. At tolerated doses, DBDx suppressed the growth of human hepatocellular carcinoma BEL-7402, HepG2, and lung adenocarcinoma A549 xenografts by 94.5%, 93.7% and 96.9%, respectively. Clonogenic assay demonstrated that DBDx showed weak cytotoxicity. Western blot showed that Flk1 and Nos3 were down-regulated in the DBDx-treated group. Proteomic analysis showed that DBDx mainly affected the metabolic process and immune system process; in addition, the angiogenesis and VEGF signaling pathway were also affected. Conclusively, DBDx, a multifunctional drug combination of three low-cytotoxic drugs, shows synergistic and highly potent antitumor efficacy evidently mediated by the modulation of tumor microenvironment. Based on its low-cytotoxic attributes and its broad-spectrum antitumor therapeutic efficacy, this multifunctional combination might be useful in the treatment of cancers, especially those refractory to conventional chemotherapeutics.

Abstract A216: Combination schedule optimization through preclinical PK-efficacy modeling of an investigational novel-novel combination: A case study of MLN0128 an mTORC1/2 inhibitor with MLN1117 a PI3Kα isoform selective inhibitor.

Abstract Schedule selection for novel combination therapy in oncology poses a daunting array of choices, such as whether to optimize each agent's schedule individually or to select dosing schedules to enhance the concomitant overlap in exposures. While combination dose schedules could be optimized empirically in the clinic, this would typically require large and expensive trials to accurately determine differences between response rates. Here we describe the utilization of preclinical in vivo tumor growth models combined with mathematical modeling techniques to translate dose schedule selection of two in-pathway inhibitors. We applied these techniques to determine the contribution of concomitant dosing of the novel combination of MLN0128 and MLN1117, investigational inhibitors of mTORC1/2 and PI3Kα respectively. Tumor Growth Inhibition (TGI) assessment of the combination was made in a diverse panel of human tumor xenografts. The combination and single agents were delivered on schedules with different degrees of dosing overlap. Isobolograms were first constructed from the in vivo TGI data and this analysis demonstrated that in most models, the overall effect of the combination on growth rate across dose schedule was additive, suggesting that co-dosing would not be a significant factor on the overall effect. To test this directly, multiple linear regressions were used to assess the degree of efficacy derived from exposure to each agent alone in contrast to the amount derived from concomitance in exposure. This regression analysis also showed that the combination efficacy did not require concomitant exposure. Finally, the lack of requirement for concomitance was corroborated using a dynamic model capturing the rates of tumor growth. This parsimonious model provided a clear fit to the observed tumor volumes, and demonstrated no requirement for concomitant dosing for combination efficacy to be obtained in the preponderance of xenograft models. Taken together, these analyses suggest that in a variety of genetic xenograft backgrounds, the effect of combining a mTORC1/2 and a PI3Kα inhibitor on efficacy is greater than each single agent alone, is additive with respect to tumor growth rate, and that concomitance of dosing is not needed to achieve maximal efficacy of the combination. This affords future trials with this combination to focus on optimization of schedule by minimizing overlapping on-mechanism tolerability concerns to achieve the greatest therapeutic benefit. These techniques illustrate a quantitative approach to using preclinical TGI data to inform early clinical dose and schedule selection of novel-novel combinations. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A216. Citation Format: Christopher Zopf, Mayank Patel, Ekta Kadakia, Robyn Fabry, Arijit Chakravarty, Swapan Chowdhury, Jing-Tao Wu, Wen Chyi Shyu, Mark Manfredi, Fabian Zohren, Chirag Patel, Keisuke Kuida, Natasha Iartchouk, Rachael Brake, Jerome Mettetal. Combination schedule optimization through preclinical PK-efficacy modeling of an investigational novel-novel combination: A case study of MLN0128 an mTORC1/2 inhibitor with MLN1117 a PI3Kα isoform selective inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A216.

Namitecan: a Hydrophilic Camptothecin with a Promising Preclinical Profile

Camptothecins are still among the most widely prescribed and effective anticancer drugs. Unfortunately, important drawbacks including water insolubility, lactone instability, reversibility of the drug-target interaction, drug resistance and toxicity are responsible for treatment failure and often require suspension of the drug administration itself. In order to overcome such drawbacks, several options in chemical manipulation of natural camptothecin have been explored, and effective compounds have been identified in a novel series of 7-oxyiminomethyl derivatives. Among the compounds of this series, the hydrophilic derivative namitecan (7 (2-aminoethoxy) iminomethyl camptothecin) has been selected for further development. The relevant features of namitecan are: 1) marked cytotoxic potency - likely related to multiple factors, including i) a potent inhibition of topoisomerase I, ii) a persistent stabilization of the cleavable complex, iii) an increased intracellular accumulation, and iv) a peculiar subcellular localization; 2) enhanced lactone stability and favorable pharmacokinetics; 3) remarkable antitumor efficacy in a large panel of human tumor xenografts (including tumor models relatively resistant to topotecan and irinotecan), particularly on squamous cell carcinomas. The clinical development of namitecan is currently ongoing. Namitecan exhibited an acceptable toxicity profile, with neutropenia being the dose-limiting toxic effect, and clinical benefit was appreciable in patients with different tumor types, particularly bladder and endometrium carcinomas. In this article, we review the relevant features of namitecan, with particular reference to its advantages compared with the two analogues (topotecan and irinotecan) approved for clinical use.

Abstract 2523: BRAF is not the only predictor of sensitivity in vitro and in vivo for TAK-733, a selective potent inhibitor of MEK1/2

Abstract MEK has emerged as an attractive target for pharmacologic intervention in cancer as the RAS/RAF/MEK/ERK cascade has proven to play a central role in the signaling required for cellular transformation and proliferation. Inhibition of MEK impacts a diverse array of additional cellular events, including differentiation, apoptosis, and angiogenesis. Identification of an orally active inhibitor of MEK which shows significant efficacy as a mono-therapy for the treatment of cancer would be ideal. TAK-733 is a potent non-ATP competitive allosteric inhibitor of MEK1/2 with IC50 values for the inhibition of MEK1/2 signaling of 2-5 nM at high (400 μM) and low (10 μM) ATP concentrations. TAK-733 was selective for mammalian MEK-1/2 in a panel of 71 enzyme assays. These included phosphodiesterases, 17 kinases (IC50 values >25 µM), cyclases, and 14 other enzymes (IC50 values >10 µM). Using an MTS (a tetrazolium salt) viability assay, TAK-733 was found to inhibit proliferation of numerous cancer cell lines expressing BRAF, KRAS, NRAS, PI3K, MEK1, EGFR mutations, cMET amplification, and wild type MAPK signaling with EC50 values ranging from 2 to 90 nM. A quantitative PK/PD relationship was established in the HT-29 human colorectal carcinoma murine xenograft model. This model showed a range of PD activity (ie, from no effect to maximum effect) which correlated well with tumor and plasma TAK-733 concentrations. The relationship between TAK-733 plasma concentration (PK) and target modulation (PD) was evaluated by modeling percent inhibition of tumor ERK phosphorylation and plasma TAK-733 concentrations at 4 hours postdose, using an inhibitory sigmoidal concentration response model. The plasma EC50 was calculated to be 45 ng/mL. TAK-733 exhibited broad-spectrum in vivo antitumor activity against a panel of human tumor xenografts with and without mutations in the MAPK pathway. These xenografts were of colon (COLO 205/ BRAF V600E and HT-29/ BRAF V600E/PI3K P449T), NSCLC (A549/ KRAS G12S, PC-9/ EGFRΔE746-A750, NCI-H1975/ EGFR L858R T790M), AML (HL-60/ NRAS), cholangio-carcinoma (EGI-1/ KRAS G12D) and melanoma (A375/ BRAF V600E) origins. A high incidence of tumor regressions was observed in this collection of cancer models. Collectively, preclinical pharmacology studies indicate TAK-733 is a specific inhibitor of MEK with the potential to significantly impair growth of a large number of cancers relying on the MAPK signaling cascade for growth and survival. and provides a strong rationale for study of this agent in clinical trials. 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 2523.

Architectural Heterogeneity in Tumors Caused by Differentiation Alters Intratumoral Drug Distribution and Affects Therapeutic Synergy of Antiangiogenic Organoselenium Compound

Tumor differentiation enhances morphologic and microvascular heterogeneity fostering hypoxia that retards intratumoral drug delivery, distribution, and compromise therapeutic efficacy. In this study, the influence of tumor biologic heterogeneity on the interaction between cytotoxic chemotherapy and selenium was examined using a panel of human tumor xenografts representing cancers of the head and neck and lung along with tissue microarray analysis of human surgical samples. Tumor differentiation status, microvessel density, interstitial fluid pressure, vascular phenotype, and drug delivery were correlated with the degree of enhancement of chemotherapeutic efficacy by selenium. Marked potentiation of antitumor activity was observed in H69 tumors that exhibited a well-vascularized, poorly differentiated phenotype. In comparison, modulation of chemotherapeutic efficacy by antiangiogenic selenium was generally lower or absent in well-differentiated tumors with multiple avascular hypoxic, differentiated regions. Tumor histomorphologic heterogeneity was found prevalent in the clinical samples studied and represents a primary and critical physiological barrier to chemotherapy.

Preclinical efficacy of ST1976, a novel camptothecin analog of the 7-oxyiminomethyl series

In previous studies, we have documented the potential therapeutic advantages of camptothecin analogs modified at the 7-position, i.e., 7-oxyiminomethyl derivatives. The present study was performed to explore the therapeutic potential of novel hydrophilic derivatives of this series. With one exception (ST1976), the tested camptothecins exhibited a reduced antiproliferative activity and all compounds retained ability to stabilize the topoisomerase I-mediated cleavable complex. The two analogs (ST1976 and ST1968) characterized by the presence of a free amino group in the side chain also exhibited the formation of persistent cleavable complexes. The most potent compound, ST1976 (7-(4-aminobenzyl)oxyiminomethylcamptothecin), was selected for evaluation of its preclinical profile of antitumor activity in a large panel of human tumor xenografts. As expected on the basis of the introduction of a hydrophilic substituent, the novel camptothecin was a substrate for BCRP. However, in spite of an apparent recognition by BCRP, ST1976 was effective following oral administration. The antitumor activity was evaluated using various schedules and routes of administration (i.v. and p.o.). ST1976 exhibited a remarkable activity in all tested tumors and was effective in a number of tumors which are resistant to irinotecan. The biological and pharmacological profile of ST1976 supports the therapeutic potential of camptothecins containing hydrophilic substituents at the 7-position. On the basis of its excellent activity in preclinical models, ST1976 is a promising candidate for clinical development.

Complete regression of xenografted human carcinomas by a paclitaxel–carboxymethyl dextran conjugate (AZ10992)

Clinically available taxanes, such as paclitaxel and docetaxel, represent one of the most promising classes of anticancer agents, despite their toxicity. To improve their pharmacological profiles, AZ10992 was synthesized based on the concept that a rational design of a polymer–drug conjugate would increase the efficacy of the parent drug. This prodrug is a paclitaxel–carboxymethyl dextran conjugate (molecular weight 150,000 g/mol) via a gly–gly–phe–gly linker. The in vivo antitumor study using AZ10992 against colon26 carcinoma cells, resistant to paclitaxel, supported this concept. Additionally, the comparative efficacy studies of AZ10992 and paclitaxel using a panel of human tumor xenografts in nude mice showed the advantages of drug–polymer conjugation. The maximum tolerated dose of AZ10992 was more than twice as high as the MTD of paclitaxel. A repeated intravenous administration of AZ10992 at 30 mg/kg/day (five injections for 4-days) showed complete regression of MX-1 mammary carcinoma xenografts. Also, HT-29 colorectal tumor xenografts, which are highly refractory to paclitaxel, showed complete regression after AZ10992 administered at 30 mg/kg/day (seven injections for 4-days). Pharmacokinetic studies showed that there were significant increases in the amount and the exposure time of total paclitaxel in the tumors after intravenous administration of AZ10992, which explains the enhanced efficacy of AZ10992.

MEN4901/T-0128, a New Camptothecin Derivative–Carboxymethyldextran Conjugate, Has Potent Antitumor Activities in a Panel of Human Tumor Xenografts in Nude Mice

The purpose of the present study was to evaluate the antitumor activity and pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human tumor xenografts in comparison with irinotecan (CPT-11) and T-2513. We have determined the antitumor activity of MEN4901/T-0128, CPT-11, and T-2513 in BALB/cA Jcl nude mice bearing human gastric (H-81), colon (H-110), lung (Mqnu-1, H-74), esophageal (H-204), liver (H-181), and pancreatic (H-48) cancer lines, which had been serially transplanted s.c. and maintained in nude mice, and characterized the pharmacokinetic profile of MEN4901/T-0128 in nude mice bearing human gastric carcinoma St-4. MEN4901/T-0128 administered i.v. showed a marked antitumor activity in each of these tumor models, producing tumor shrinkage in the models of H-204 and H-181 carcinomas at its maximum tolerated dose of 80 mg/kg (expressed as T-2513) weekly for 4 weeks (q7d x 4) and tumor-shrinking or marked growth-inhibitory effects in the models of H-81, H-110, Mqnu-1, H-74, and H-48 carcinomas at 1/3 of its maximum tolerated dose (q7d x 4). Pharmacokinetic analysis showed that MEN4901/T-0128 had an extended plasma half-life with sustained tumor levels of T-2513, which may explain the superior activity of MEN4901/T-0128 in vivo. Because the efficacies of some drugs in this human cancer-nude mouse panel correlated well with their clinical outcomes in patients with the same type of cancers, the findings provide direct support that MEN4901/T-0128 is more efficacious than CPT-11 and is an excellent candidate for clinical trials for the treatment of solid tumors.

Gimatecan, a novel camptothecin with a promising preclinical profile.

The realization that position 7 of camptothecin allows several options in chemical manipulation of the drug has stimulated a systematic investigation of a variety of substituents in this position. These efforts resulted in the identification of a novel series of 7-oxyiminomethyl derivatives. Among compounds of this series we have selected a promising lipophilic derivative, gimatecan, for further development. The relevant features of gimatecan are: (i) marked cytotoxic potency, likely related to multiple factors, including a potent inhibition of topoisomerase I, a persistent stabilization of the cleavable complex, an increased intracellular accumulation and a peculiar subcellular localization; (ii) lack of recognition by known resistance-related transport systems; (iii) increased lactone stability and favorable pharmacokinetics; (iv) good oral bioavailability; and (v) an impressive antitumor efficacy in a large panel of human tumor xenografts, with various treatment schedules. Phase I clinical studies with oral administration support the preclinical results of the novel camptothecin. Using different schedules and dosing durations, gimatecan exhibited an acceptable toxicity profile, with myelotoxicity being the dose-limiting toxic effect. An appreciable number of tumor responses was achieved and favorable pharmacokinetics with a very long terminal half-life was observed. The clinical development of gimatecan is currently ongoing, with phase II studies in diverse tumor types (colon, lung, breast carcinoma and pediatric tumors).

Enhanced therapeutic effects of doxorubicin and paclitaxel in combination with liposome-entrapped ends-modified raf antisense oligonucleotide against human prostate, lung and breast tumor models

Raf-1 protein kinase plays an important role in cell growth, proliferation and cell survival. We have previously described the use of liposome-entrapped antisense raf oligonucleotide (LErafAON) to inhibit Raf-1 expression resulting in tumor growth inhibition and radiosensitization. The present study was undertaken to evaluate the chemosensitization effects of LErafAON in combination with doxorubicin or paclitaxel on a panel of human tumor xenografts. LErafAON (25.0 mg/kg i.v. x 10) displayed significant antitumor activity (P<0.05) when administered as a single agent in prostate (PC-3), lung (A549) and breast (MDA-MB 231) carcinoma models. Doxorubicin (1.0-4.0 mg/kg i.v. per week x 3) and paclitaxel (1.0-4.0 mg/kg i.v. on alternate days x 3) were administered as single agents at non-toxic doses that led to only minimal to moderate antitumor activity. However, a combination of LErafAON with doxorubicin or paclitaxel led to significantly enhanced antitumor activity in all the tumor types tested (PC-3, P<0.03; A549, P<0.035; MDA-MB 231, P<0.045) as compared with LErafAON alone or chemotherapeutic agents alone treated groups. This effect of chemosensitization appeared to be sequence-specific because a mismatch control oligonucleotide continued to show significant tumor growth. Additionally, no inhibition in Raf-1 expression in MDA-MB 231 tumor tissue was observed with mismatch oligonucleotide treatment. On the other hand, LErafAON treatment led to >75% inhibition of Raf-1 expression in tumor tissue. These preclinical observations support the use of LErafAON in combination with chemotherapeutic agents to improve the treatment of human cancers.

Antitumour and antiangiogenic effects of IDN 5390, a novel C-seco taxane, in a paclitaxel-resistant human ovarian tumour xenograft.

IDN 5390 is a novel C-seco taxane analogue selected for preclinical development on the basis of its antimotility activity on endothelial cells, antitumour efficacy in a large panel of human tumour xenografts and high tolerability in mouse. On the basis of oral availability, IDN 5390 is suitable for protracted administration schedules. Such a treatment schedule has been reported as the most appropriate to exploit the antiangiogenic effects of cytotoxic drugs. An ability to downregulate angiogenesis-related growth factors in tumour cells has been described for IDN 5390. The aim of the study was to investigate the antitumour and antiangiogenic potential of oral IDN 5390 on a human ovarian carcinoma xenograft, the INT.ACP/PTX, resistant to paclitaxel (PTX). Such tumour line was derived in vivo from a cisplatin-resistant tumour line, the A2780/DDP, which is sensitive to PTX. Compared to the parental cells, INT.ACP/PTX cells exhibited a high level of Pgp expression, resulting in a reduced in vitro sensitivity to both PTX and IDN 5390. The INT.ACP/PTX tumour xenograft was still resistant to PTX, but responsive to IDN 5390, when delivered per os, by a daily prolonged schedule. A direct effect on tumour cells, allowed by the high tolerability of the compound in mouse, cannot be excluded in vivo. Immunohistochemical analysis indicated a significant reduction of microvessel density in IDN 5390-treated tumours, lasting till 7 days after the last drug administration. Thus, a prolonged inhibitory effect on tumour angiogenesis is consistent with the persistent growth control of INT.ACP/PTX tumour achieved by IDN 5390. On the contrary, the low tolerability and the limited oral availability of conventional taxanes do not allow an easy feasibility of such treatment regimen. Thus, the tolerability profile of IDN 5390 in preclinical systems and its efficacy in PTX-resistant tumours support the therapeutic interest for its clinical development, with particular attention to oral daily prolonged schedules.

213 MEN4901/T-0128: a new camptothecin derivative-carboxymethyldextran conjugate with potent anti-tumor activities in a panel of human tumor xenografts in nude mice

213 MEN4901/T-0128: a new camptothecin derivative-carboxymethyldextran conjugate with potent anti-tumor activities in a panel of human tumor xenografts in nude mice

In vivo antitumor activity of F 11782, a non-intercalating dual catalytic inhibitor of topoisomerases I and II, against a panel of human tumor xenografts

The marked in vivo antitumor activity of F 11782 against murine experimental tumors (Kruczynski et al., Br J Cancer 83: 1516-24, 2000) has now been confirmed in a panel of human tumor xenografts. Using an intermittent schedule of six administrations over 2 weeks, F 11782 showed major activity in four of eight xenograft models. Excellent activity was noted versus the CAKI-1 (renal) model, with regressions at the two highest doses, and marked activity against DLD-1 (colon) xenografts, also resulting in regressions at the MTD. Marked antitumor activity was also observed against DU 145 (prostate) and GLC4 (small-cell lung) tumors. At optimal doses, significant T/C values ranged from 3 to 29%, with significant growth delays of 1.5-5.6, without major body weight loss. This tumor growth inhibition induced by F 11782 was sustained with time for > or = 6 weeks post implant. In contrast, no real activity was recorded against NCI-H460 (non small-cell lung) tumors and only minor responses, with optimal T/C values of < 42%, noted in the rapidly proliferating SF-295 (CNS) and LOX IMVI (melanoma) xenografts or the chemo-refractory LoVo (colon) model. Overall, this study showing a 50% response rate with definite antitumor activity across a broad spectrum, coupled with its unique mechanistic profile, has prompted the further development of F 11782.

Genotyping of NAD(P)H:quinone oxidoreductase (NQO1) in a panel of human tumor xenografts: relationship between genotype status, NQO1 activity and the response of xenografts to Mitomycin C chemotherapy in vivo

Pharmacogenetic analysis of polymorphisms in drug metabolizing enzymes is currently generating considerable interest as a means of individualizing patient therapy. Recent studies have suggested that patients that are homozygous for a polymorphic variant (a C to T transition at position 609 of the cDNA sequence) of the enzyme NAD(P)H:quinone oxidoreductase (NQO1) may be resistant to Mitomycin C (MMC). Genotyping of a panel of 54 human tumor xenografts by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), classified tumors as wild type (40/54), heterozygotes (11/54), and homozygous mutants (3/54). Previously, 37 of these tumors had been characterized in terms of their response to MMC in vivo, and in this study, a further nine tumor xenografts have been characterized in terms of their response to MMC. No correlation could be found between the NQO1 polymorphic status of xenografts and their response to MMC in vivo. In terms of genotype/phenotype relationships, NQO1 activity in tumors genotyped as wild type, heterozygotes, and homozygous mutants were 311.1 ± 421.9 (N = 40), 76.9 ± 109.5 (N = 11), and 0.2 ± 0.17 (N = 3) nmol/min/mg, respectively. Genotyping of patients may provide a useful initial step in identifying patients who are unlikely to benefit from quinone-based chemotherapy. In the case of MMC, however, the work presented here demonstrates that genotyping of individuals with respect to NQO1 is unlikely to be beneficial in terms of predicting tumor responses to MMC.

Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice.

Camptothecins have emerged as an important new class of antitumor drugs. Camptothecin derivatives such as CPT-11 and topotecan are commercially available and approved for the treatment of colorectal (CPT-11) and ovarian and small-cell lung cancer (topotecan). This study was designed to test the efficacy of karenitecin, a novel highly lipophilic camptothecin derivative, against a panel of human tumor xenografts derived from adult and pediatric central nervous system malignancies growing in athymic nude mice. Xenografts evaluated were derived from childhood high-grade gliomas (D-212 MG, D-456 MG), adult high-grade gliomas (D-54 MG, D-245 MG), medulloblastomas (D-341 MED, D-487 MED), and ependymomas (D-528 EP, D-612 EP), as well as sublines with demonstrated resistance to procarbazine (D-245 MG (PR)) and busulfan (D-456 (BR)). In replicate experiments, karenitecin was given at 1.0 mg/kg per dose via intraperitoneal injection for a period of 10 consecutive days, which is the dosage lethal to 10% of treated animals. Karenitecin produced statistically significant (P < or = 0.001) growth delays in all subcutaneous xenografts tested, including the sublines resistant to procarbazine and busulfan. Growth delays ranged from 12.1 days in D-456 MG (BR) to 90+ days in D-212 MG and D-341 MED. Karenitecin also produced statistically significant (P < or = 0.001) increases in survival of animals bearing D-341 MED intracranial xenografts (69% increase) and those bearing D-456 MG xenografts (62% increase). These preclinical studies confirm that karenitecin is active against human central nervous system xenografts and should undergo clinical evaluation in patients with malignant central nervous system tumors.

Tissue distribution, antitumour activity and in vivo apoptosis induction by MEN10755 in nude mice

MEN10755 is a disaccharide analogue of doxorubicin (DXR) endowed with a broader spectrum of activity compared with DXR in a panel of human tumour xenografts. In an attempt to investigate the pharmacological basis of the improvement of therapeutic efficacy of the analogue, a comparative pharmacokinetic (tissue and tumour distribution) and pharmacodynamic (antitumoral activity and ability to induce apoptosis) study of MEN10755 and DXR was performed in athymic nude mice bearing a human ovarian carcinoma xenograft (A2780). Drug level was quantified by high performance liquid chromatography (HPLC) with fluorimetric detection after a single intravenous (i.v.) injection of 7 mg/kg of MEN10755 or DXR. The results indicated a reduced accumulation of MEN10755 compared with DXR in all tissues investigated (tumour, heart, kidney and liver). The reduction was more marked in normal than tumour tissues. Moreover, in spite of the reduced drug uptake by tumour tissues, the new disaccharide anthracycline given in its optimal regimen showed an enhanced antitumour efficacy, compared with DXR. The drug effects on tumour growth paralleled a marked activation of apoptosis. In conclusion, the pattern of tissue distribution and the pharmacokinetic behaviour were consistent with a better tolerability of the novel analogue which allowed a higher cumulative dose to be delivered. The superior therapeutic efficacy of the analogue over DXR, in spite of a reduced tumour accumulation, supports an increased tumour selectivity.

Efficacy and toxicity profile of oral topotecan in a panel of human tumour xenografts

On the basis of their mechanism of action (cell killing during DNA replication) and the potential reversibility of the drug effects, protracted therapy with camptothecins is reported to provide optimal antitumour effects. Furthermore, oral administration may be a useful modality for optimisation of treatment. The aim of this study was to compare the therapeutic profile of topotecan given orally or intravenously in human tumours xenografted into athymic nude mice. The drug topotecan was given according to an intermittent (every fourth day, four times) or daily (qd×5/weekly×5−10 weeks; only orally) schedule. Tumour growth inhibition and persistence of drug effects were assessed and compared with untreated mice. In a panel of seven tumour xenografts, oral topotecan was at least as effective on three and significantly more effective on four tumours. Using the intermittent schedule, the maximum tolerated dose (MTD) was comparable for the two routes (15 mg/kg), but the toxicity profile suggested a better tolerability in terms of lethal effects after oral administration. The daily oral treatment of low drug doses allowed a higher cumulative dose to be delivered with improved antitumour efficacy (2/10 cured in a large cell lung cancer) and no evidence of toxicity. In spite of the low bioavailability of oral topotecan (23.5%), the persistent plasma levels of the drug suggest that the time of exposure to the drug is more critical than the plasma concentrations for antitumour efficacy. This interpretation is consistent with the increased efficacy of prolonged daily treatment with low-dose levels. The results may have implications for the future design of clinical studies.

DIAGNOSTIC UROLOGY AND TESTIS CANCER

No AccessJournal of UrologyUROLOGICAL SURVEY: Abstracts1 Dec 1999DIAGNOSTIC UROLOGY AND TESTIS CANCER Jerome P. RichieM.D. Jerome P. RichieJerome P. Richie More articles by this author View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)68163-3AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail References 1 : A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts. Cancer Res.1999; 59: 1036. Google Scholar © 1999 by American Urological Association, Inc.FiguresReferencesRelatedDetails Volume 162Issue 6December 1999Page: 2222-2227 Advertisement Copyright & Permissions© 1999 by American Urological Association, Inc.MetricsAuthor Information Jerome P. Richie More articles by this author Expand All Advertisement PDF downloadLoading ...