Cancer Research

ALZET Research Alert - April 2015

Header ImageBefore a cancer therapeutic is selected for clinical development, scientists must fully characterize its mechanism of action, antitumor activity, and dosing parameters in preclinical animal studies. For nearly 40 years, ALZET® Osmotic Pumps have been used in cancer studies as a reliable and convenient method for continuous dosing of unrestrained lab animals. These small, implantable pumps deliver solutions at controlled rates over prolonged periods, enabling compound levels to be maintained within their therapeutic range to maximize efficacy with lower drug doses and reduce adverse effects and drug toxicity. Read on for recent cancer research describing the use of ALZET pumps. Contact ALZET Technical Services for more information at 800.692.2990 or alzet@durect.com.

COX-2/sEH inhibition suppresses tumor growth and metastasis
Cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH) have critical roles in angiogenesis and tumorigenesis. Zhang et al. developed a first-in-class, dual inhibitor of COX-2 and sEH (PTUPB), and evaluated its therapeutic impact on tumor growth and metastasis in mice. ALZET pumps (Model 2004) were used for continuous dosing of PTUPB for 4 weeks to overcome its oral bioavailability limitations. Continuous PTUPB treatment resulted in 70-83% tumor inhibition in the NDL primary tumor model, and 61-67% lung weight reduction in the LLC metastatic tumor model. PTUPB suppressed tumor growth and metastasis by inhibiting tumor angiogenesis, as confirmed by reduced VEGF plasma levels and inhibited endothelial cell proliferation in NDL tumors. PTUPB treatment was shown to inhibit the COX-2 and sEH pathways in vivo. The study proposes the use of dual COX-2/sEH inhibitors as potential cancer therapy with minimal toxicity.
PNAS 2014;111(30):11127-11132

Combination therapy for B-cell lymphoma
Researchers at Astellas Pharma Inc. investigated the therapeutic potential of sepantronium bromide (YM155) in combination with bendamustine and/or rituximab in murine xenograph models of diffuse large B-cell lymphoma (DLBCL). Tumor bearing mice were treated with YM155 alone by continuous SC infusion using ALZET pumps (Model 1007D), or in combination with IV bolus injections of bendamustine and/or rituximab. In human DLBCL DB xenografts, combination of YM155 with bendamustine induced complete tumor regression without affecting body weight. In SU-DHL-8 disseminated xenografts, triple combination therapy with YM155, bendamustine and rituximab prolonged overall survival compared with double combination therapy. The study supports the use of triple combination therapy with YM155, bendamustine and rituximab for patients with relapsed/refractory DLBCL.
Clin Cancer Res 2014;20(7):1814-1822

New peptides target hypothalamic GnRH regulation to treat prostate cancer
Takeda’s Lupron Depot broke ground as the first FDA approved product for controlled release of a peptide, the GnRH analogue, leuprolide. A new study from Takeda describes the use of ALZET pumps to evaluate two peptide analogues of kisspeptin, which is a hypothalamic peptide and regulator of GnRH neurons. Rats received ALZET pumps delivering TAK-448, TAK-683, leuprolide or vehicle for 4 weeks. Testosterone levels were compared with animals receiving the same compounds by daily injection and with orchiectomized animals. Continuous infusion required far lower daily doses than did daily injection. Both new compounds produced a shorter testosterone flare and more dramatic reduction in testosterone levels as compared with leuprolide. TAK-683 was also evaluated in the JDCaP tumor xenograft model. Plasma PSA levels, followed as a proxy for tumor growth, were suppressed more quickly by TAK-683 than leuprolide given by continuous infusion.
Eur J Pharm 2014;735:77-85

Targeted therapy for pancreatic tumors
The cell surface enzyme γ-Glutamyltransferase (γGT) has been found to be overexpressed in pancreatic tumor cells and tumor-activated stellate cells. Ramsay et al. explored the possibility of targeting pancreatic tumor cells with GSAO, an arsenical prodrug that is activated to enter endothelial cells by γGT. ALZET pumps (Model 1004) were used for continuous SC administration of GSAO to nude mice bearing pancreatic tumors. Continuous administration of GSAO resulted in significant inhibition of tumor growth and angiogenesis after the 28-day treatment period. The antitumor efficacy of GSAO was positively correlated with γGT tumor activity, such that inhibition of tumor growth and vascularity was significantly higher in tumors expressing high levels of γGT compared to those expressing lower levels. These findings indicate that γGT can be used to target pancreatic tumor cells with cancer therapeutics.
Mol Pharmaceutics 2014;11:1500-1511

Ruthenium-gamma-linolenic acid complex effective against glioma
Platinum-based drugs (i.e., cisplatin and carboplatin) have been used to treat glioblastomas (GBM), but they have been shown to be cytotoxic to normal cells. Miyake et al. combined the anti-tumor properties of ruthenium and gamma-linolenic acid (GLA) into a single novel drug (Ru2GLA), and investigated its therapeutic effects in the C6 rat glioma model. ALZET pumps (Model 2002) and brain infusion kits were used for continuous ICV infusion of Ru2GLA, GLA, or vehicle (aCSF) for 14 days. Ru2GLA treatment strongly inhibited C6 cell proliferation, altered vessel integrity and induced distinct changes in tumor cell morphology. Furthermore, Ru2GLA treatment was “well-tolerated as the animals showed no visible signs of serious side-effects related to the direct infusion of the compounds to the brain”. The study concluded that “Ru2GLA appears to be a low-toxicity drug and a potential candidate for anti-proliferative therapy of glioma”.
Anticancer Res 2014;34:1901-1912

Carboplatin and radiation therapy improve survival in glioma model
Carboplatin is an effective drug for clinical cancer therapy, but has not been effective in patients with high grade gliomas due to its systemic toxicity, high water solubility, and inability to effectively cross the blood-brain barrier (BBB). Yang et al. investigated the therapeutic efficacy of carboplatin combined with radiotherapy (RT) in the F98 glioma rat model. Tumor bearing rats were treated with carboplatin by continuous ICV infusion using ALZET pumps (Model 2001) for 7 days, or by convection enhanced delivery (CED), with or without RT. The best survival data, with no treatment-related toxicity, was seen in animals receiving continuous carboplatin delivery by ALZET pumps plus RT with a mean survival time (MST) of 107.7 ± 20.7 days, as compared with CED of carboplatin with RT (MST = 83.6 ± 21.5 days), or RT alone (MST = 35.3 ± 1.8 days).
Radiat Oncol 2014;9:25-33

Anti-EGFR immunotoxin therapy for brain tumors
The EGF receptor gene (EGFR), and its deletion mutant, EGFRvIII, are frequently overexpressed in glioblastoma. Chandramohan et al. tested the preclinical efficacy of D2C7-(scdsFv)-PE38KDE, a recombinant immunotoxin reactive with the 55-amino acid region of the extracellular domain of EGFRwt and EGFRvIII. Following continuous, intracranial infusion of the immunotoxin for 3 and 7 days using ALZET pumps, Chandramohan observed “significant increase in survival at a very low dose…” in NSG mice. ALZET pumps enabled the researchers to achieve high local concentration and homogenous distribution of the immunotoxin at the tumor site, strategies shown to be effective in the treatment of glioblastoma. The study suggests that this immunotoxin displays significant potential for treating brain tumors expressing either EGFRwt, EFGRvIII, or both.
Clin Cancer Res 2013;19(17):4717-27

P-glycoprotein limits brain distribution of trametinib
Dabrafenib combined with trametinib is an approved therapy for advanced melanoma; however, poor brain distribution limits its efficacy on brain metastasis. Vaidhyanathan et al. investigated the factors influencing the brain distribution of trametinib in transgenic mouse models. ALZET pumps (Model 1003D) were used to evaluate the steady-state brain and plasma distribution of trametinib following continuous intraperitoneal infusion for 48 hours. In vitro studies showed that trametinib is a substrate for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), efflux transporters found at the blood-brain barrier (BBB). In vivo studies showed that the trametinib brain-to-plasma ratios were significantly higher in P-gp knockout and Bcrp knockout mice compared to wild-type mice. These data validated the role of P-gp and Bcrp in restricting brain distribution of trametinib due to active efflux at the BBB, with P-gp playing a greater role than Bcrp.
Drug Metab Dispos 2014;42(8):1292-1300

Melanoma tumor response to bevacizumab and BNCT
A study by Masunaga et al. shows that boron neutron capture therapy (BNCT) combined with bevacizumab, a VEGF inhibitor, can sensitize total tumor cells [proliferating (P) + quiescent (Q)], and reduce the number of lung metastases to a similar level as the acute hypoxia-releasing agent, nicotinamide. The study was designed to evaluate the local tumor response by analyzing the effect of treatment on the total tumor cell population (P + Q). ALZET pumps were used for continuous labeling of all P tumor cells following continuous administration of bromodeoxyuridine (BrdU) into B16-BL6 melanoma tumor-bearing mice. Tumor cells not incorporating BrdU following continuous labeling were regarded as Q cells.
Exp Ther Med 2014;8:291-301

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What researchers are saying...

“CsA and RAD were administered by ALZET minipumps, which we prefer because of the well-defined drug exposure. It avoids the daily peaks and troughs of oral drug administration, which in many animal studies are not well defined.” Matsumoto et al., Trasplantation 2003;76:166-1170.