Green tea constituent (--)-epigallocatechin-3-gallate inhibits topoisomerase I activity in human colon carcinoma cells.

DNA topoisomerases I and II are essential for cell survival and play critical roles in DNA metabolism and structure. Inhibitors of topoisomerase constitute a novel family of antitumor agents with demonstrated clinical activity in human malignancies. The clinical use of these agents is limited due to severe toxic effects on normal cells.

Increased sensitivity of human colon cancer cells to DNA cross-linking agents after GRP78 up-regulation.

We have shown earlier that pre-treatment of V79 Chinese hamster cells with 6-aminonicotinamide (6-AN) or 2-deoxyglucose (2-dG) results in over-expression of the Mr 78,000 glucose-regulated stress protein (GRP78) and the subsequent development of resistance to inhibitors of topoisomerase II. These phenomena also occur in V79-derived cell lines that are deficient in poly(ADP-ribose) (p(ADPR)) metabolism. In contrast, over-expression of GRP78 under the conditions outlined above is found to be associated with hypersensitivity to several clinically-relevant DNA cross-linking agents, namely, 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, and melphalan.

Hypersensitivity to DNA cross-linking agents associated with up-regulation of glucose-regulated stress protein GRP78.

We have shown previously that NAD/poly(ADP-ribose) polymerase-deficient cells that overexpress Mr 78,000 glucose-regulated stress protein (GRP78) are resistant to topoisomerase II inhibitors, such as etoposide, m-amsacrine, and doxorubicin. However, these cells have been found to be hypersensitive to DNA cross-linking agents, including melphalan, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). These observations prompted us to examine whether overexpression of GRP78 is associated with modulation of cytotoxicity of clinically useful DNA-cross-linking agents such as melphalan, BCNU, and cisplatin.

Insulin and insulin-like growth factor-1 (IGF-1) inhibit repair of potentially lethal radiation damage and chromosome aberrations and alter DNA repair kinetics in plateau-phase A549 cells.

Plateau-phase A549 cells exhibit a high capacity for repair of potentially lethal radiation damage (PLD) when allowed to recover in their own spent medium. Addition of either insulin or insulin-like growth factor-1 (IGF-1) to the spent medium 60 to 120 min before irradiation significantly inhibits PLD repair. The 9-h recovery factor (survival with holding/survival without holding) is reduced from 10.

Comparison of the effects of hydralazine on tumor and normal tissue blood perfusion by MRI.

Purpose: The differential effects on blood perfusion of the vasodilator hydralazine (HYD) between tumor and normal muscle have been measured using the dynamic enhanced-magnetic resonance imaging (DE-MRI) technique.

Methods And Materials: DE-MRI is a noninvasive method of determining blood perfusion in tumors and normal tissues using the MR contrast agent Gd-DTPA. Hydralazine is currently being used in an attempt to increase tumor response to bioreductive agents and to hyperthermia.

Determination of changes in tumor blood perfusion after hydralazine treatment by dynamic paramagnetic-enhanced magnetic resonance imaging.

Magnetic resonance imaging, using the paramagnetic chelate gadopentetate dimeglumine as a perfusing agent, was used to investigate the effect of the vasoactive drug hydralazine on tumor blood perfusion. The method requires measurements of the magnetic resonance image intensity changes with time on a pre-selected region of interest in the tumor image, immediately following intravenous injection of gadopentetate dimeglumine. The present study showed that the initial slope of the intensity-time curve can be used, to a first approximation, to infer tumor blood perfusion.

The dependence of proton longitudinal and transverse relaxation times on cell-cycle phase: mouse MCA-transformed 10T1/2 TCL-15 cells.

Attempts to determine proton NMR longitudinal relaxation times (T1) as a function of cell-cycle stage using cells synchronized by chemical methods have yielded conflicting results (P. T. Beall, C.

The response of the KHT sarcoma to radiotherapy as measured by water proton NMR relaxation times: relationships with tumor volume and water content.

The potential application of magnetic resonance imaging (MRI) to predict tumor response to radiotherapy is investigated. The water proton spin-lattice and spin-spin relaxation times (T2 and T2, respectively) of murine sarcomas (designated KHT) were measured shortly after excision. This study has demonstrated significantly different responses in T1 and T2 between the control and the irradiated tumors at various times following single doses of X rays.

Radiation damage to dinucleoside monophosphates: mediated versus direct damage.

The mediation of radiation-induced damage to dinucleoside monophosphate by oxygen and by glutathione was studied. The sequence isomers d(TpA) and d(ApT) were X-irradiated in aqueous solutions and the products isolated by reverse-phase high-performance liquid chromatography. The main products were characterized by proton NMR spectroscopy.

Radiation chemistry of a dinucleoside monophosphate and its sequence isomer.

A combination of high-performance liquid chromatography (HPLC) and nuclear magnetic resonance (NMR) spectroscopy was used to analyze the products of X-irradiated aqueous solutions of the dinucleoside monophosphate thymidylyl(3'-5')-2'-deoxyadenosine, d(TpA), and its sequence isomer 2'-deoxyadenylyl(3'-5')thymidine, d(ApT). The products of d(TpA) include both bases and nucleotides and a variety of thymine modifications of d(TpA) including the two cis and two trans glycol stereoisomers, two cis monohydroxy derivatives, an N-formamide derivative, and the hydroxymethyl derivative. Attention is focused on using NMR spectral features to distinguish among the various stereoisomers.

HPLC-n.m.r. studies of radiation damage to d(TpA).

Nine of the products isolated from X-irradiated aqueous solutions of d(TpA) by HPLC are identified from their proton n.m.r.