Anti-tumor effects of AMT in the renal cell carcinoma model.

Auron-Misheil-Therapy (AMT) is a defined but unique combination of approved pharmaceuticals. It consists of insulin, chlorpheniramine and an aqueous camomile extract, and it has been successfully applied clinically in late-stage cancer patients. The purpose of this study was to elucidate the anti-tumor efficacy of AMT in a validated murine renal cell carcinoma animal model (RENCA). There were two independent studies; each animal group consisted of 16 mice. During a 6-week pretreatment period, vehicle (group A) and AMT (1.6 mg/kg/d) (group B) were administered once daily in a 5 days/week schedule either intramuscularly or subcutaneously. Tumor challenge at day 0 was followed by a 3-week treatment period (either vehicle or AMT once daily intramuscularly for 21 days consecutively). In study 2 the AMT dosage was increased up to 4-fold by doubling individual doses and switching to a twice daily schedule. The injections were all intramuscular. With the exception of group D, a six-week pretreatment period preceded the tumor challenge at day 0. Tumor challenge was followed by a 3-week treatment period (vehicle, AMT at either 3.2 mg/kg/d) (group A) or 6.4 mg/kg/d (group B), or AMT0, an AMT preparation which does not stimulate IL-6 secretion (6.4 mg/kg/d, group C) continuously for 21 days. AMT administration for group D (6.4 mg/kg/d) was limited to the treatment period from day 1 to 21. All mice were sacrificed 21 days after tumour transplantation. AMT administration was safe and well tolerated, and significantly reduced primary tumor volume in pretreated animals. The effective route of application was intramuscular, with dose escalation resulting in an improved anti-tumor effect. This is the first demonstration of a significant anti-tumorigenic effect of AMT in a validated tumor model.

Mode of action and clinical impact of VEGF signaling inhibitors.

The established role of VEGF signaling in promoting tumor angiogenesis has led to the development and clinical validation of several agents that selectively target this pathway in patients with advanced-stage malignancies. These include neutralizing anti-VEGF monoclonal antibodies, soluble VEGF receptors and small-molecule inhibitors of VEGF receptor function, administered either as monotherapy or in combination with chemotherapy. Several modes of action have been identified, such as inhibition of new vessel growth, regression of newly formed vasculature, alteration of tumor vessel function and direct effects on tumor cells. VEGF-targeting drugs currently play an important role in the treatment of cancer and their impact will probably further increase in the future.

Molecular targeted therapies for solid tumors: management of side effects.

This review will provide physicians and oncologists with an overview of side effects related to targeted agents that inhibit vascular endothelial growth factor (VEGF), epidermal growth factor (EGF) and mammalian target of rapamycin (mTOR) signaling in the treatment of solid tumors. Such targeted agents can be divided into monoclonal antibodies, tyrosine kinase inhibitors, multitargeted tyrosine kinase inhibitors and serine/threonine kinase inhibitors. Molecular targeted therapies are generally well tolerated, but inhibitory effects on the biological function of the targets in healthy tissue can result in specific treatment-related side effects, particularly with multitargeted agents. We offer some guidance on how to manage adverse events in cancer patients based on the range of options currently available.

Antitumoral and antiangiogenic efficacy of bisphosphonates in vitro and in a murine RENCA model.

BACKGROUND: Bisphosphonates have shown direct antitumoral activity in vitro, in vivo and even in clinical studies, but the exact mechanism for this has not yet been elucidated. In this study the antiangiogenic potency of zoledronic acid and clodronate were evaluated. MATERIALS AND METHODS: The effects of zoledronic acid and clodronate on the proliferation of endothelial cells and different tumor cells, and on the activity of protein kinases were investigated. Furthermore in vitro experiments were performed to evaluate the underlying antiangiogenic mechanism of action. Both bisphosphonates were examined in vivo at different doses and in daily subcutaneous application in a murine renal cell carcinoma model (RENCA). The antiangiogenic activity was evaluated by immunohistochemical staining (CD31) and by determination of mouse vascular endothelial growth factor (VEGF) serum concentration. RESULTS: Zoledronic acid and clodronate inhibited proliferation of endothelial cells at lower concentrations than the different tumor cell lines did. This effect was more pronounced for zoledronic acid. The activity of almost all tested kinases was inhibited by zoledronic acid, whereas clodronate showed no effect. In the RENCA model, a significant effect of zoledronic acid on the primary tumor in a bell-shaped dose response curve with the highest efficacy between 100 Bg/kg 2xd and 200 Bg/kg 1xd, was observed. The mean vessel density (MVD) was significantly reduced by both bisphosphonates at different concentrations. This is the first report on increased mouse VEGF serum concentrations in the RENCA model. CONCLUSION: The results indicate that these bisphosphonates, particularly zoledronic acid, possess antitumoral and antiangiogenic activity.

Development of albumin-binding doxorubicin prodrugs that are cleaved by prostate-specific antigen.

Prostate-specific antigen (PSA) is a serine protease that is overexpressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. In this work, we developed albumin-binding prodrugs with the structures MT-Ser-Ser-Tyr-Tyr- Ser-Gly-DOXO, MT-Asn-Ser-Ser-Tyr-Phe-Gln-DOXO (MT = maleimidotriethyleneglycol acid; DOXO = Doxorubicin) or EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO (EMC = epsilon-maleimidocaproic acid; X = amino acid). The maleimide Doxorubicin derivatives bound rapidly to the cysteine-34 position of endogenous and exogenous albumin and were efficiently cleaved by PSA at the P(1)-P'(1) scissile bond, releasing a respective Doxorubicin dipeptide (Ser-Gly-DOXO or Phe-Gln-DOXO). The derivative containing arginine residues (EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO) exhibited excellent water solubility for intravenous administration. Subsequent biological evaluation was focused on a PSA-negative xenograft model (PC 3) and a PSA-positive xenograft model (CWR22) in order to assess the selectivity of our therapeutic approach. EMC-Arg-Arg-Ser-Ser-Tyr-Tyr-Ser-Gly-DOXO showed no in vivo activity in the PSA-negative PC 3 model, but good activity in the CWR22 PSA-positive model that was comparable to Doxorubicin.

ZD-6126 AstraZeneca.

AstraZeneca is developing ZD-6126, one of the ANG-400 series of vascular-targeting and tubulin-binding agents under license from Angiogene Pharmaceuticals Ltd, for the potential treatment of cancer.