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Results: 4

1.
Fig. 3

Fig. 3. From: Increased Tumor Oxygenation and Drug Uptake During Anti-Angiogenic Weekly Low Dose Cyclophosphamide Enhances the Anti-Tumor Effect of Weekly Tirapazamine.

Plot of % individual deviation of pO2 versus tumor volume estimated from the mixed model described in Materials and Methods. Each point of the graph represents one mouse. There is a strong negative correlation (−0.81) between these two variables on an individual basis.

J.C. Doloff, et al. Curr Cancer Drug Targets. ;9(6):777-788.
2.
Fig. 4

Fig. 4. From: Increased Tumor Oxygenation and Drug Uptake During Anti-Angiogenic Weekly Low Dose Cyclophosphamide Enhances the Anti-Tumor Effect of Weekly Tirapazamine.

Expression profiles of factors involved in tumor angiogenesis during metronomic chemotherapy. Relative levels of rat VEGF, TSP-I, PLGF, HIF-1α, and mouse VEGF receptors 1 and 2 in 9L tumors were quantified by real-time PCR (qPCR) using SYBR Green 1 chemistry following the second of two weekly CPA treatments (140mg/kg i.p.). Total RNA was isolated from frozen tumor samples (0.1–0.4 g) using TRIzol reagent according to the manufacturer’s protocol. Ct values determined for each mRNA were normalized to the 18S rRNA content of each RNA sample and are plotted as fold increase over untreated tumor samples. Data are represented as mean ± SE relative mRNA levels of at least four individual tumors per group. *: p< 0.05 and **: p< 0.01.

J.C. Doloff, et al. Curr Cancer Drug Targets. ;9(6):777-788.
3.
Fig. 1

Fig. 1. From: Increased Tumor Oxygenation and Drug Uptake During Anti-Angiogenic Weekly Low Dose Cyclophosphamide Enhances the Anti-Tumor Effect of Weekly Tirapazamine.

A, Expression of mouse TSP-1 mRNA was measured in the days following the second of two weekly CPA treatments (140mg/kg i.p.). TSP-1 expression is presented as fold increase over untreated tumor samples. Metronomic CPA induced more than 8-fold increase in endothelial TSP-1 above the untreated level, Mean ± SE n=4 individual tumors per group. B, Changes in tissue pO2 of subcutaneous 9L tumors in the experimental group. The mice were administered CPA (140mg/Kg, i.p.) on day 0, day 7 and day 14 and the changes in tumor pO2 were repeatedly measured by EPR oximetry, Mean ± SD, n = 6. C, Change in tumor volume of the experimental group, n = 6. D, Lack of change in tissue pO2 of 9L tumors in the control group injected with phosphate buffered saline. Mean ± SD, n = 5 and E, Control group volume measurement, n = 5. F, The expression of rat Glut-1 mRNA was measured in the days following the second of two weekly CPA treatments (140mg/kg i.p.). Metronomic CPA induced a 4-fold increase in rat Glut-1 expression above the untreated level, Mean ± SE n=4 individual tumors per group. Statistical comparisons using a two-tailed Student’s test were performed using Prism software version 4 (Graph-Pad Software, San Diego, CA), *: p< 0.05 and **: p < 0.01.

J.C. Doloff, et al. Curr Cancer Drug Targets. ;9(6):777-788.
4.
Fig. 2

Fig. 2. From: Increased Tumor Oxygenation and Drug Uptake During Anti-Angiogenic Weekly Low Dose Cyclophosphamide Enhances the Anti-Tumor Effect of Weekly Tirapazamine.

Rat 9L gliosarcoma tumors were grown in scid mice. When the tumor size reached 1 cm3, CPA was injected as a single dose at 140mg/Kg BW i.p. every 7 days (day 0 corresponds to 7 days after one CPA injection, and day 1, 2 or 3 correspond to 1, 2, or 3 days after the 2nd of two CPA injections). A, To assess drug entry in tumors after CPA treatment, the amount of 4-OH-CPA in the blood and tumors were measured in animals killed 15 min after injection of a small test dose of 50 mg/kg CPA i.p. at day 0, 1,2, and 3 after the second CPA injection. Cardiac blood and tumor homogenates (n=4 tumors) were processed to determine their content of activated CPA. *: p< 0.05 and **: p< 0.01. B, Activated CPA metabolite, CPA activation by tumor extracts was assayed as previously described [24]. C, P450 reductase activity was assayed using 20 μg of tumor extracts, lysed by sonication and then assayed for P450R-catalyzed, NADPH-dependent cytochrome C reduction (DA550) at 30°C. Cytotoxicity assays – Cells were plated in triplicate at 4000 cells/well of a 48-well plate 18–24 hr prior to drug treatment. D, Cells treated with CPA (0 to 500 μM) were incubated for 4 days under normoxia. E, Cells treated with TPZ (0 to 5 μM), were incubated for 4 days in a tissue culture incubator maintained under hypoxic conditions 1% O2, or under normoxic conditions 19.6% O2. Cell viability after this time was determined using a crystal violet/alcohol-extraction assay. Data are presented as cell number relative to drug-free controls, mean ± SD.

J.C. Doloff, et al. Curr Cancer Drug Targets. ;9(6):777-788.

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