Tumor Blood Flow Rate Research Articles

Physiologically Based Pharmacokinetic Modeling for Prediction of 5-FU Pharmacokinetics in Cancer Patients with Hepatic Impairment After 5-FU and Capecitabine Administration.

5-fluorouracil (5-FU) and its prodrug capecitabine are commonly prescribed anti-tumor medications. We aimed to establish physiologically based pharmacokinetic (PBPK) models of capecitabine-metabolites and 5-FU-metabolites to describe their pharmacokinetics in tumor and plasma of cancer patients with liver impairment. Models including the cancer compartment were developed in PK-Sim® and MoBi® and evaluated by R programming language with 25 oral capecitabine and 18 intravenous 5-FU studies for cancer patients with and without liver impairment. The PBPK models were constructed successfully as most simulated Cmax and AUClast were within two-fold error of observed values. The simulated alterations of tumor 5-FU Cmax and AUClast in cancer patients with severe liver injury compared with normal liver function were 1.956 and 3.676 after oral administration of capecitabine, but no significant alteration was observed after intravenous injection of 5-FU. Besides, 5-FU concentration in tumor tissue increases with higher tumor blood flow but not tumor size. Sensitivity analysis revealed that dihydropyrimidine dehydrogenase (DPD) and other metabolic enzymes' activity, capecitabine intestinal permeability and plasma protein scale factor played a vital role in tumor and plasma 5-FU pharmacokinetics. PBPK model prediction suggests no dosage adaption of capecitabine or 5-FU is required for cancer patients with hepatic impairment but it would be reduced when the toxic reaction is observed. Furthermore, tumor blood flow rate rather than tumor size is critical for 5-FU concentration in tumor. In summary, these models could predict pharmacokinetics of 5-FU in tumor in cancer patients with varying characteristics in different scenarios.

DCE-MR imaging of orbital lesions: diagnostic performance of the tumor flow residence time τ calculated by a multi-compartmental pharmacokinetic tumor model based on individual factors.

Differentiating benign from malignant orbital lesions by imaging and clinical presentation can be challenging. To differentiate benign from malignant orbital masses using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) based on tumor flow residence time τ calculated with the aid of a pharmacokinetic tumor model. Sixty patients with orbital masses were investigated by 3-T MRI including dynamic sequences. The signal intensity-time curve after i.v. contrast medium administration within lesions was approximated by Gd-concentration profiles on the basis of model calculations where the tumor is embedded in a whole-body kinetic model. One output of the model was tumor flow residence time τ, defined as the ratio of the tumor volume and the tumor blood flow rate. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic performance of τ. The results were compared with those of Ktrans, kep, ve, iAUC, and ADC. Thirty-one benign and 29 malignant orbital masses were identified (reference standard: histopathology, clinical characteristics). Mean τ was significantly longer for benign masses (94 ± 48 s) than for malignant masses (21 ± 19 s, P < 0.001). ROC analysis revealed the highest area under the curve (AUC = 0.94) for τ in orbital masses compared to standard methods. Tumor flow residence times τ of benign and malignant orbital masses are valuable in the diagnostic work-up of orbital tumors. Measures of diagnostic accuracy were superior for τ compared to ADC, Ktrans, ve, and iAUC.

A Mobile Positron Activation Detection System for Post–Proton Therapy Tumor Blood Flow Measurements

Positron emission nuclei of 15O, 13N, and 11C are created inside tumors during patients’ proton therapy treatment. With 70 to 85% of human tissues water content and approximately 50 Molar O2 in blood, detection of 15O positron decay can be used to measure the tumor blood flow rate. This is a washout technique with a non-invasive radioactive tracer injection. A coincidence photon detection system was developed to measure the 15O activity change to deduce tumor blood flow rate. Systematic experimental validations of the system were conducted to evaluate its performance in measuring flow rates of proton irradiated water and carbon phantoms.

SU-E-CAMPUS-J-06: Development of a Tumor Blood Flow Measurement System for Proton Therapy Patients

Purpose: To develop a tumor blood flow rate measurement system utilizing positron emission after proton therapy for potential evaluation of the efficacy of radiotherapy, concurrent chemotherapy and/or antiangiogenesis therapy of proton therapy patients. Method: Daily proton treatment generates positron emission nuclei, i.e., 15O, 13N and 11C inside the treated volume of patients. In‐room measurement of activities of 15O as a function of time right after proton treatment can directly measure tumor blood flow rate due to the biological washout characteristics. A pair of NaI2 detectors and coincidence detection electronics were obtained. The NaI2 detectors were mounted on a modified C‐arm for good axial alignment and flexible isocentric rotation. The detector energy spectrum was calibrated using 60Co, 137Cs and 22Na sources. The energy window was set for 511 keV peaks. Current system is not optimized for collimation and shielding. The system performance was evaluated using 18F‐FDG. Proton irradiated water and/or ice were also measured for positron emission activity and the acquired data were analyzed. Detector shielding and collimation is under construction. IRB approval for proton patient blood flow rate measurement was obtained for evaluation of their tumor blood flow rates and changes over treatment course. Results: The C‐arm based detector platform demonstrated precise alignment and great flexibility for different treatment sites. The 18F‐FDG decay measurement using the system showed the measured half life is within 16s of the theoretical value. Activity measurement of proton irradiated water and ice showed about 10s half life difference between the measured and theoretical value. This was potentially due to the activation inside the water/ice container and lack of detector collimation and shielding. Conclusions: A non‐invasive in‐room tumor blood flow rate measurement system for proton therapy patients is under development. The preliminary data is reported. American Cancer Society Chris DiMarco Institutional Research Grant

Abstract 3362: Miniaturized PBPK model improves pharmacodynamic characterization and physiological interpretability for compounds with profound hysteresis in tumor.

Abstract Background: Significant hysteresis between plasma concentration and target inhibition at the effect site (e.g., tumor) is a frequent observation, commonly described mathematically by connecting the central (i.e., plasma) compartment to an ‘effect compartment’ by a ‘link’ which causes the concentration in the latter to be delayed relative to the plasma. The result is a direct response between effect-compartment concentration and target inhibition. A significant drawback is that the effect compartment cannot be observed (making it impossible to validate) and has no physiological interpretation (rendering communication with other disciplines difficult). We develop a novel approach that is more physiologically meaningful, provides more-precise model parameter estimates, and gives insight into the physico-chemical factors limiting distribution into the tumor. Method: We orally administered single doses of several compounds (including Crizotinib, AZD3463, and others) targeting ALK to mice bearing tumors derived from the DEL and H3122 non-small-cell lung cancer line, at several dose levels. At 6, 24, and 48 hours post-dose, we measured the plasma and tumor concentrations of each compound and associated target inhibition (phosphorylated ALK, pALK) in the tumor. pALK inhibition shows a direct response not to plasma, but to tumor concentration, indicating that the delay is distributional in nature. We constructed a miniature physiologically-based pharmacokinetic (mPBPK) model consisting of a central compartment and a tumor of fixed physiological volume. pALK inhibition was modeled as a direct Emax response to tumor concentration. For each compound, we simultaneously fitted the mPBPK model to the naïve-pooled plasma and tumor concentrations, as well as pALK, using all available dose levels. Beyond the standard PK and PD parameters (Emax, E0, IC50) we also fitted the tumor partition constant Kp, and tumor blood flow rate Qt. For comparison, we fitted a standard effect-compartment (‘link’) model to the plasma concentrations and pALK levels to the same data. Results: For each compound, we computed unbound EC50 for both effect-compartment and mPBPK models. We found that while the point estimates largely agree, the mPBPK model delivers more-precise estimates (typically 50% lower CV%). We attribute this to its use of additional data (tumor concentration) to constrain the model, which more than compensates for the additional parameters in the mPBPK model. We find that there is broad consistency in estimates of tumor flow rate Qt across the compounds studied, indicating that distribution from plasma to site of action is limited by blood flow, rather than by permeability. Additionally, we found that the greater physiological interpretability of the mPBPK model enhances cross-functional communication within project teams. Citation Format: Francis D. Gibbons, Dan Widzowski, Minhui Shen, Jane Cheng, Lisa Drew, Jamal C. Saeh, Douglas Ferguson. Miniaturized PBPK model improves pharmacodynamic characterization and physiological interpretability for compounds with profound hysteresis in tumor. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3362. doi:10.1158/1538-7445.AM2013-3362

The Tuberous Sclerosis Complex Regulates Trafficking of Glucose Transporters and Glucose Uptake

Human cancers often display an avidity for glucose, a feature that is exploited in clinical staging and response monitoring by using (18)F-fluoro-deoxyglucose (FDG) positron emission tomography. Determinants of FDG accumulation include tumor blood flow, glucose transport, and glycolytic rate, but the underlying molecular mechanisms are incompletely understood. The phosphoinositide-3 kinase/Akt/mammalian target of rapamycin complex (mTORC) 1 pathway has been implicated in this process via the hypoxia-inducible factor alpha-dependent expression of vascular endothelial growth factor and glycolytic enzymes. Thus, we predicted that tumors with elevated mTORC1 activity would be accompanied by high FDG uptake. We tested this hypothesis in eight renal angiomyolipomas in which the loss of tuberous sclerosis complex (TSC) 1/2 function gave rise to constitutive mTORC1 activation. Surprisingly, these tumors displayed low FDG uptake on positron emission tomography. Exploring the underlying mechanisms in vitro revealed that Tsc2 regulates the membrane localization of the glucose transporter proteins (Glut)1, Glut2, and Glut4, and, therefore, glucose uptake. Down-regulation of cytoplasmic linker protein 170, an mTOR effector, rescued Glut4 trafficking in Tsc2(-/-) cells, whereas up-regulation of Akt activity in these cells was insufficient to redistribute Glut4 to the plasma membrane. The effect of mTORC1 on glucose uptake was confirmed using a liver-specific Tsc1- deletion mouse model in which FDG uptake was reduced in the livers of mutant mice compared with wild-type controls. Together, these data show that mTORC1 activity is insufficient for increased glycolysis in tumors and that constitutive mTOR activity negatively regulates glucose transporter trafficking.

Measurement of tumor blood flow using colored dye extraction microspheres in two rat tumor models

A technique that can measure tumor blood flow easily, accurately and economically is required to study tumor angiogenesis and angiogenesis inhibition. Using dye extraction colored microspheres, we measured tumor blood flow in Sato lung carcinoma (SLC) and ascites hepatoma LY80 in rats. Colored microspheres were infused into tumor-bearing rats via a catheter in the left ventricle. After removal of the tumor and the liver, the tissue samples were dissolved, and the microspheres were isolated. Dye was extracted, and the dye concentration was quantified by spectrophotometry. The dye concentration per gram of tumor was compared with that per gram of liver as follows (AU = absorbency units): [AU per gram of tumor] / [AU per gram of liver] X 100 = (%). Tumor blood flow corrected for wet weight was calculated as follows: [blood flow to tumor] = [AU per gram of tumor] X [reference withdrawal rates / [AU per gram of reference blood]. Tumor blood flow rate was divided by tumor weight to yield ml.min. -1 g -1 . The tumors were also examined histologically, and casts of the tumor vasculature were prepared with silicone rubber. Blood flow 2 weeks after transplantation was equivalent to 1/10 and 1/2 at 1 week in SLC and LY80 tumors, respectively (SLC, P=0.009, n=10; LY80, P=0.05, n=10). These decreases in tumor blood flow were associated with underlying pathological and vascular change. Blood flow in LY80 tumors negatively correlated with tumor volume (P=0.009, n=10). We concluded that the colored microsphere method, initially developed to measure organ blood flow, is also useful for estimating tumor blood flow in rats.

Measurement of tumor blood flow using colored dye extraction microspheres in two rat tumor models.

A technique that can measure tumor blood flow easily, accurately and economically is required to study tumor angiogenesis and angiogenesis inhibition. Using dye extraction colored microspheres, we measured tumor blood flow in Sato lung carcinoma (SLC) and ascites hepatoma LY80 in rats. Colored microspheres were infused into tumor-bearing rats via a catheter in the left ventricle. After removal of the tumor and the liver, the tissue samples were dissolved, and the microspheres were isolated. Dye was extracted, and the dye concentration was quantified by spectrophotometry. The dye concentration per gram of tumor was compared with that per gram of liver as follows (AU = absorbency units): [AU per gram of tumor] / [AU per gram of liver] X 100 = (%). Tumor blood flow corrected for wet weight was calculated as follows: [blood flow to tumor] = [AU per gram of tumor] X [reference withdrawal rate] / [AU per gram of reference blood]. Tumor blood flow rate was divided by tumor weight to yield ml. min-1g-1. The tumors were also examined histologically, and casts of the tumor vasculature were prepared with silicone rubber. Blood flow 2 weeks after transplantation was equivalent to 1/10 and 1/2 at 1 week in SLC and LY80 tumors, respectively (SLC, P=0.009, n=10; LY80, P=0.05, n=10). These decreases in tumor blood flow were associated with underlying pathological and vascular change. Blood flow in LY80 tumors negatively correlated with tumor volume (P=0.009, n=10). We concluded that the colored microsphere method, initially developed to measure organ blood flow, is also useful for estimating tumor blood flow in rats.

Optimization of antitumor effect of liposomally encapsulated doxorubicin based on simulations by pharmacokinetic/pharmacodynamic modeling

It has been reported that long circulating liposomes enhanced the antitumor effect of doxorubicin (DOX) by increasing delivery of DOX to tumor tissues. However, there is no quantitative information on the relationship between the antitumor effect and liposomal characteristics governing the release rate of entrapped drugs, although the importance of drug release-rate control from liposomes has been pointed out. Here, we developed a physiological model for free and liposomal DOX to calculate the time course of free DOX in the extracellular space and linked this with a cell kill kinetic model to quantify the antitumor effect of DOX. Simulations were performed to clarify the relationship between antitumor effect and pharmacokinetic or physicochemical parameters of liposomes, as well as pharmacological or physiological parameters of tumor tissues. The importance of long circulation time of liposomes was confirmed. The optimum rate of drug release from long circulating liposomes was found at the release rate constant of around 0.06 h−1. This optimum value was not dependent on the tumor proliferation time, sensitivity of tumor cells to DOX, or the tumor blood flow-rate. This simulation indicated that the optimization of the delivery to tumor tissue by long circulating liposomes could be possible by changing the release rate of DOX for the maximum antitumor effect.

Blood Flow Rate in Normal and Tumor-bearing Rats in Conscious State, under Urethane Anesthesia, and during Systemic Hypothermia

The blood flow rates of 14 tissues in the body were determined by microsphere method using normal and tumor-bearing rats kept conscious or under urethane anesthesia. The effects on the blood flow rate in the tissues were assessed for multimodal therapy, systemic hypothermia for ischemic brain injury, and local hyperthermia and angiotensin II-induced hypertensive chemotherapy for cancer. Urethane anesthesia showed no effect on cardiac output, while there was a tendency of decrease of blood flow rate and % of cardiac output in each tissue other than muscle tissue, in which they increased as a counterbalance, in normal and tumor-bearing rats. Systemic hypothermia gave results similar to those of urethane anesthesia in normal rats, but for tumor-bearing rats, it decreased cardiac output, and consequently the blood flow rate in most tissues. Brain blood flow rate was about half of that in the conscious rats. Local hyperthermia also decreased the cardiac output and blood flow rate in each tissue, including the tumor tissue. Angiotensin II-induced hypertension showed no effect on cardiac output, had various effects on blood flow rate in each tissue, and led to no increase in the tumor blood flow rate. Simulations based on the physiological pharmacokinetic modeling suggested that intramuscular injection of a lung-specific derivative of ceftazidime would provide the ideal biodistribution to ensure its optimal therapeutic efficacy during systemic hypothermia. This methodology, namely the pharmacokinetic simulation based on the physiological values of the body, will provide a useful piece of information on drug delivery systems under various conditions.

Reduced Adriamycin Concentration in Rat Mammary Tumors Treated Previously with Hyperthermia

The effect of prior hyperthermia on the concentrations of adriamycin in tumors was examined. Chemically induced (9,10-dimethyl-1,2-benzanthracene) rat mammary adenocarcinomas were not heated or were heated one or two times (43.5 degrees C, 1 h; 24 h apart when two times) using an Nd:YAG laser. Rats were administered adriamycin (5 mg/kg, iv) 3 h after hyperthermia treatment. The concentrations of adriamycin in plasma and tissue were determined using high-performance liquid chromatography. Although plasma pharmacokinetics was unchanged by prior local hyperthermia, the concentration of adriamycin was significantly lower in tumors that had been heated previously compared to that in unheated tumors. Tumor blood flow rate was determined after an identical heating protocol using a reference sample technique with 113Sn microspheres. Tumor blood flow rate increased slightly during hyperthermia and then rapidly returned to control levels after hyperthermia. Decreased concentrations of adriamycin in tumors may result from biochemical changes induced by hyperthermia in neoplastic cells and may explain the adriamycin resistance in thermotolerant cells reported previously.

Tumor Blood Flow-Characterization, Modifications, and Role in Hyperthermia

Abstruct-The differential blood flow rateof normaland tumor tissues plays a critical role in determining the effectiveness of hyperthermia alone or in combination with radiation and chemotherapy. The objective of this paper is to summarize the data on tumor blood flow rate during normothermia and hyperthermia, and to discuss the use of pharmacological agents in modifying the tumor blood flow rate for therapeutic benefits. After a brief review of various physical, physiological, biochemical, and biological factors that determine the effectiveness of hyperthermia in cancer treatment, various methods of blood flow measurements will be outlined. The following section will be devoted to the tumor blood flow rate during normothermia. Next will be discussion of changes in tumor blood flow rate at elevated temperatures. Finally, the possibility of modifying tumor blood flow rate by the use of vasoactive agents will be discussed. Throughout this paper, outstanding problems in the measurements and alterations of blood flow will be identified and some directions for future research will be suggested.