Cancer research
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Dynamic studies of Gd-based contrast agents in magnetic resonance imaging (MRI) are increasingly being used for tumor characterization as well as therapy response monitoring. Because detailed knowledge regarding the pathophysiological properties, which in turn are responsible for differences in contrast enhancement, remains fairly undetermined, it was the aim of this project to: (a) examine the relationship between contrast-enhanced dynamic MRI-derived characteristics and histological microvessel density counts, a recognized surrogate of tumor angiogenesis, from primary or recurrent cancers of the uterine cervix; and (b) correlate these parameters with lymphatic involvement to characterize tumor aggressiveness in terms of lymphatic spread. Pharmacokinetic parameters (amplitude, A; exchange rate constant, k21) were calculated from a contrast-enhanced dynamic MRI series in 55 patients (ages 25-72 years; mean, 50 years) with biopsy-proven primary (n = 42) or recurrent (n = 13) uterine cervical cancer. ⋯ Pharmacokinetic MRI-derived parameters (A and k21) increased with increasing histological microvessel density counts with r = 0.41 and 0.50, respectively. Lymphatic involvement was more comprehensibly assessed by the pharmacokinetic parameter k21 compared with histological microvessel density, resulting in a higher sensitivity, overall accuracy, and comparable specificity. Contrast-enhanced MRI parameters might prove to be applicable for estimation of tumor angiogenesis in uterine cervical cancer; thus, MRI may become an additional tool to characterize malignant progression in terms of lymphatic involvement in uterine cervical cancer.
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pH-mediated conversions in the structure of the topoisomerase (topo) I inhibitors camptothecin (CPT) and its analogues have strong implications for the pharmacokinetics and pharmacodynamics of these novel anticancer agents. Because the cell-penetrating and biologically active lactone isomers predominate at acidic conditions, we have tested if low pH potentiates the cytotoxic and antitumor effects of CPT and its water-soluble derivative topotecan (TPT). In L1210 leukemia cells, rapid initial uptake of radiolabeled CPT and TPT was followed by a gradual release from cells at physiological pH 7.4, whereas high drug levels were maintained in cells at pH 6.2. ⋯ In accordance with the pH optimum for TPT uptake at pH 6.8 to 6.4, tumor acidification had no effect on the antitumor effect of this analogue. By contrast, the intervention significantly potentiated the response of tumors to CPT. The results indicate that local pH is an important determinant of the cellular pharmacokinetics and the antitumor activity of CPT and analogues.
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Beta-L-Dioxolane-cytidine (BCH-4556) is a novel anticancer nucleoside analogue with a stereochemically unnatural beta-L configuration. This compound was previously shown to have a potent antitumor activity in human prostate and hepatocellular xenograft tumor models (K. L. ⋯ BCH-4556 efficacy evaluation in the orthotopic subrenal capsule tumor models demonstrated a potent tumor growth inhibition against human CAKI-1 xenografts and tumor stasis against mouse Renca tumors. BCH-4556 was also effective in inhibiting the growth of rebound CAKI-1 tumors after the administration of a second treatment cycle. The observed antitumor activity of BCH-4556 in several RCC human solid tumor xenografts, including the lethal RXF-393 model, warrants further investigation of this novel nucleoside analogue in clinical trials of RCC.