Strategies to Increase Drug Penetration in Solid Tumors.

Strategies to increase drug penetration in solid tumors.

Front Oncol. 2013; 3: 193
Choi IK, Strauss R, Richter M, Yun CO, Lieber A

Despite significant improvement in modalities for treatment of cancer that led to a longer survival period, the death rate of patients with solid tumors has not changed during the last decades. Emerging studies have identified several physical barriers that limit the therapeutic efficacy of cancer therapeutic agents such as monoclonal antibodies, chemotherapeutic agents, anti-tumor immune cells, and gene therapeutics. Most solid tumors are of epithelial origin and, although malignant cells are de-differentiated, they maintain intercellular junctions, a key feature of epithelial cells, both in the primary tumor as well as in metastatic lesions. Furthermore, nests of malignant epithelial tumor cells are shielded by layers of extracellular matrix (ECM) proteins (e.g., collagen, elastin, fibronectin, laminin) whereby tumor vasculature rarely penetrates into the tumor nests. In this chapter, we will review potential strategies to modulate the ECM and epithelial junctions to enhance the intratumoral diffusion and/or to remove physical masking of target receptors on malignant cells. We will focus on peptides that bind to the junction protein desmoglein 2 and trigger intracellular signaling, resulting in the transient opening of intercellular junctions. Intravenous injection of these junction openers increased the efficacy and safety of therapies with monoclonal antibodies, chemotherapeutics, and T cells in mouse tumor models and was safe in non-human primates. Furthermore, we will summarize approaches to transiently degrade ECM proteins or downregulate their expression. Among these approaches is the intratumoral expression of relaxin or decorin after adenovirus- or stem cell-mediated gene transfer. We will provide examples that relaxin-based approaches increase the anti-tumor efficacy of oncolytic viruses, monoclonal antibodies, and T cells. HubMed – drug

Influence of the duration of intravenous drug administration on tumor uptake.

Front Oncol. 2013; 3: 192
Fouliard S, Chenel M, Marcucci F

Enhancing tumor uptake of anticancer drugs is an important therapeutic goal, because insufficient drug accumulation is now considered to be an important reason for unresponsiveness or resistance to antitumor therapy. Based on a mechanistic tumor uptake model describing tumor exposure to molecules of different molecular size after bolus administration, we have investigated the influence of the duration of intravenous administration on tumor uptake. The model integrates empirical relationships between molecular size and drug disposition (capillary permeability, interstitial diffusivity, available volume fraction, and plasma clearance), together with a compartmental pharmacokinetics model and a drug/target binding model. Numerical simulations were performed using this model for protracted intravenous drug infusion, a common mode of administration of anticancer drugs. The impact of mode of administration on tumor uptake is described for a large range of molecules of different molecular size. Evaluation was performed not only for the maximal drug concentration achieved in the tumor, but also for the dynamic profile of drug concentration. It is shown that despite a lower maximal uptake for a given dose, infusion allows for a prolonged exposure of tumor tissues to both small- and large-sized molecules. Moreover, infusion may allow higher doses to be administered by reducing Cmax-linked toxicity, thereby achieving a similar maximal uptake compared to bolus administration. HubMed – drug

Chemotherapy for advanced gastric cancer: review and update of current practices.

Gut Liver. 2013 Jul; 7(4): 385-93
Park SC, Chun HJ

No standard adjuvant or palliative chemotherapy regimen has been internationally approved for patients with advanced gastric cancer. Adjuvant chemoradiotherapy is administered prior to surgery and is used in the Unitied States, and intensified chemotherapy is administered prior to and after surgery and is used in Europe. Limited D1 dissections are also frequently performed in the United States and Europe. In Korea, patients undergoing D2 resection appear to benefit from postoperative adjuvant chemotherapy using S-1 or capecitabine plus oxaliplatin. Fluoropyrimidine, platinum, taxane, epirubicin, and irinotecan may be employed alone or in combination as a first-line therapy in a palliative chemotherapy regimen. In Asia, an orally administered fluoropyrimidine, such as capecitabine or S-1, is favored over the continuous infusion of 5-fluorouracil because of its convenience. Trastuzumab has been integrated into the current standard chemotherapy for human epidermal growth factor receptor 2-overexpressing gastric cancers. There is currently no standard regimen for secondary palliative chemotherapy. Clinical studies of several targeted therapies are ongoing. HubMed – drug

Effects of different administration protocols on the plasma concentration of donepezil hydrochloride in dementia patients with stage 5 chronic kidney disease.

Nephron Extra. 2013 Jan; 3(1): 59-65
Amano C, Ito T, Egawa M, Oka T, Hanada K, Matsui K, Nabika T, Tanabe K

The prevalence of chronic kidney disease (CKD) as well as Alzheimer’s disease (AD) increases with age. With the aging of the population in Japan, there is an increasing likelihood that patients with CKD will receive donepezil hydrochloride (DPZ), an antidementia drug, in the near future. Nevertheless, there have been few reports on how to use DPZ in patients with severe CKD. We report on 2 CKD stage 5 patients who received DPZ under different prescriptions. In case 1, 3 mg/day of DPZ was initially administered for 4 months, after which the dose was increased to 5 mg/day. In case 2, 5 mg was administered twice a week. The plasma concentration of DPZ was measured and the effectiveness was assessed using the Mini-Mental Health State Examination and the Hasegawa Dementia Rating Scale. We found that (1) only a slight increase in the plasma concentration of DPZ was observed with a dose of 3 mg daily, (2) there was a significant increase in the plasma concentration with a dose of 5 mg daily, and (3) when 5 mg of DPZ was administered twice a week, the plasma concentration did not differ significantly from healthy controls who had received 5 mg daily. Although cognitive function was improved best when the 5-mg dose was administered daily with no apparent side effects, the plasma concentration came close to reaching a toxic level at this dose. Careful follow-up may be essential when DPZ is used at 5 mg/day or greater in severe CKD patients. HubMed – drug