| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Advances in Brief |
Department of Radiation Oncology, Case Western Reserve University, School of Medicine and University Hospitals of Cleveland/Ireland Cancer Center, Cleveland, Ohio 44106 [S. E. B., H-S. H., M. M., T. W. D., D. A. B., T. J. K.], and Department of Human Oncology, University of Wisconsin Medical School, Madison, Wisconsin 53792 [S. E. B., C. G., K. K., M. M.]
 |
ABSTRACT |
|---|
 Top ABSTRACT IntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
In contrast to the well-characterized, marked increase in cytotoxicity (>1 log cell kill) found with 6-thioguanine exposures in HCT116/3-6 (hMLH1+) cells compared to HCT116 (hMLH1-) cells, we found only modest cytotoxicity (10–20% cell kill) in both cell lines when treated with IdUrd or BrdUrd for 1 population doubling. Upon further analysis, the levels of halogenated dThd analogues in DNA were significantly lower (two to three times lower) in HCT116/3-6 cells than in HCT116 cells, and similar results were found in Mlh1+/+ spontaneously immortalized murine embryonic fibroblasts and fibroblasts from Mlh1 knockout mice. As a result of the higher levels of the dThd analogue in DNA, there was an increase in radiation sensitivity in HCT116 cells but not in HCT116/3-6 cells after pretreatment with IdUrd or BrdUrd when compared to treatment with radiation alone. Additionally, we found no differences in the cellular metabolic pathways for dThd analogue DNA incorporation because the enzyme activities of dThd kinase and thymidylate synthase, as well as the levels of triphosphate pools, were similar in HCT116 and HCT116/3-6 cells. These data suggest that the hMLH1 protein may participate in the recognition and subsequent removal of halogenated dThd analogues from DNA. Consequently, whereas MMR-deficient cells and tumor xenografts have shown intrinsic resistance to a large number of chemotherapeutic agents, the 5-halogenated dThd analogues appear to selectively target such cells for potential enhanced radiation sensitivity.
|
Introduction |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
, have been recognized as potential radiosensitizing agents since the early 1960s. Although they were initially synthesized as chemotherapeutic agents, these analogues demonstrated no significant clinical activity when tested in a variety of solid tumors and are not approved for clinical use as cancer chemotherapy drugs. However, over the last decade, there has been renewed interest in the clinical testing of these dThd analogues as radiosensitizers in selected cancer patient groups (1)
. Recent Phase I/II trials using prolonged continuous or scheduled intermittent i.v. infusions of BrdUrd or IdUrd before and during radiation therapy have focused principally on patients with high-grade brain tumors (2
, 3)
. The results of these recent Phase II clinical trials suggest an improved outcome compared to radiation alone. A therapeutic gain in clinical radiosensitization by these halogenated dThd analogues may also exist for metastatic colorectal cancers and unresectable sarcomas, based on the results of other recent Phase I and/or II trials (4
, 5)
. Incorporation into DNA (Fig. 1B)
is a prerequisite for radiosensitization of human tumors by the halogenated dThd analogues, and the extent of radiosensitization (up to three times) correlates directly with the percentage of dThd substitution in DNA (6)
. Another nucleoside analogue, 6-TG (Fig. 1A)
, has previously been shown to invoke a cytotoxic response in MMR-proficient cells. This analogue also becomes incorporated into DNA (Fig. 1B)
, and the extent of DNA incorporation correlates directly with cytotoxicity to 6-TG (7)
.
|
In this study, we compare the cytotoxicity of the halogenated dThd analogues IdUrd and BrdUrd to that seen with 6-TG in HCT116 and HCT116/3-6 genetically matched human colon carcinoma cell lines. We measure the percentage of dThd substitution in DNA and the in vitro radiosensitivity of these two cell lines after preirradiation exposures for 1 population doubling to clinically achievable plasma concentrations (1–10 µM) of these dThd analogues. We also determine the in vitro enzyme activities of the two rate-limiting enzymes in the de novo (TS) and salvage (TK) dThd metabolic pathways as well as the triphosphate pools to compare dThd analogue metabolism between these genetically matched human tumor cell lines. Finally, we compare incorporated IdUrd in the DNA of spontaneously immortalized MEFs established from Mlh1 knockout mice and their wild-type siblings after exposure to IdUrd for approximately 1 population doubling. We show that the 5-substituted dThd analogues are present in significantly higher levels in the DNA of MMR-deficient cells and that pretreatment with these analogues results in an increase in radiation sensitivity in HCT116 MMR-deficient cells but does not result in a significant increase in MMR-proficient HCT116/3-6 cells.
|
Materials and Methods |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
Parental HCT116 human colon carcinoma cells, HCT116/2-1 cells, and HCT116/3-6 cells were maintained in 
-MEM (Life Technologies, Inc.) supplemented with 10% fetal bovine serum (Hyclone, Logan, UT), penicillin (100 µg/ml), and streptomycin (100 µg/ml) and grown in a 95% air-5% CO2 atmosphere at 37°C. G418 (400 µg/ml; Life Technologies, Inc.) was added to maintain HCT116/3-6 and HCT116/2-1 cells, but experiments were performed in medium that did not contain G418. Our characterization of these cell lines, their population doubling times, and p53 status has been reported previously (13)
.
The MC5 MEFs contain wild-type Mlh1 (Mlh1+/+), whereas the MC3 MEFs derived from Mlh1 knockout mice are deficient in both copies of the gene (Mlh1-/-). These cells have a C57BL/6 background and were generated and generously supplied by Dr. R. M. Liskay (Oregon Health Science University, Portland, OR). Both cell lines were spontaneously immortalized and genotyped in the lab of Dr. R. M. Liskay. MC5 and MC3 fibroblasts were also maintained in -MEM supplemented with 10% fetal bovine serum and 50 µg/ml gentamicin (Life Technologies, Inc.) and grown in 95% air-5% CO2 at 37°C.
Drug and Drug Radiation Cytotoxicity.
For clonogenic survival studies after administration of drug alone, exponentially growing human tumor cells (HCT116, HCT116/3-6, or HCT116/2-1) were exposed to 1–10 µM IdUrd or BrdUrd or to 0.3–30 µM 6-TG (Sigma Chemical Co., St. Louis, MO) for 18 h (
1 cell population doubling). After the 18-h exposure, drug-free complete medium was added, and serially diluted cell populations were grown at 37°C. The surviving fraction of cells was determined using a standard colony-forming assay with appropriate controls as described previously (16)
. A surviving colony was defined as 
50 cells after 7–10 days of growth after drug treatment. For the IR survival studies, comparable populations of exponentially growing tumor cells were exposed to 0 or 5 µM IdUrd or BrdUrd for 18 h immediately before irradiation (0–6 Gy). Similar colony-forming assays and analyses were performed after 10–14 days as described previously (16)
. SERs were calculated, as described previously, at 10% survival (6)
. Irradiation was performed using a model 109 137Cs irradiator (J. L. Shepherd and Associates, Glendale, CA) using a dose rate of 5.8 Gy/min. Clonogenic survival studies after treatment with drug alone and drug plus radiation were performed in triplicate and repeated at least three times in the human tumor cell lines.
dThd Levels Present in DNA.
Exponentially growing tumor cell populations were exposed to a 4-h pulse of 1–10 µM IdUrd or BrdUrd and harvested 14 h after the addition of fresh medium, and MEFs were exposed to 1–10 µM IdUrd for 18 h at 37°C. The percentage of dThd replacement was determined using a modification of the method of Belanger et al. (17)
, as detailed previously (6)
. HPLC analysis was performed using a Waters W600 solvent delivery system with a C18-µBondclone column (3.9 x 300 mm; Phenomenex, Inc., Torrance, CA). Samples were eluted with 100 mM sodium acetate (pH 5.45) and 7% acetonitrile (mobile phase). Peaks were detected using a Waters model 745 data module. Standard curves were generated for dThd, IdUrd, and BrdUrd using authentic samples (Sigma Chemical Co.). The studies of the percentage of dThd incorporation using BrdUrd and IdUrd in exponentially growing human tumor cells and MEF cells were repeated in triplicate.
TK Activity Assay in Human Colon Cancer Cells.
TK activity was determined from cell cytosol prepared by the modification of Lee and Cheng’s original method (18)
by Fisher et al. (19)
. Briefly, exponentially growing HCT116, HCT116/3-6, and HCT116/2-1 cells were harvested, scraped, and pelleted by centrifugation at 600 x g for 10 min at 4°C. Matching cultures of cells were resuspended by trypsinization and counted to determine the specific enzyme activity per million cells. The pellet was resuspended in 2 volumes of buffer containing 5 mM Tris-HCl (pH 7.5), 10 mM KCl, 5 mM DTT, 5 mM ATP, 5 mM MgCl2, and 10% (v/v) glycerol and homogenized using a Dounce homogenizer. Cell debris was removed by centrifugation at 12,000 x g for 20 min at 4°C. The supernatant was recovered and placed on ice, and the enzyme reaction was carried out as described previously (19)
. TK activity was expressed as pmol of TMP produced/106 cells/min.
Measurement of TS Activity in Intact Human Colon Cancer Cells.
TS activity was measured in intact HCT116, HCT116/3-6, and HCT116/2-1 cells as described previously (20)
. In addition to measuring intrinsic levels of TS activity in exponentially growing cells, activity after treatment with dThd analogues was also measured. For these data, exponentially growing cells were plated and treated in 6-well cell culture plates. Treatment involved an 18-h exposure to 0 or 5 µM IdUrd or BrdUrd or a 2-h exposure to 0 or 5 µM FdUrd. FdUrd was used as a positive control because it effectively inactivates (binds) TS with shorter exposures, as reported previously by our laboratory (20)
. Cell density at the time enzyme activity was measured ranged from 1.5–2.0 x 106 cells/dish. To assay activity, the dishes were washed once with serum-free MEM. One ml of serum-free -MEM containing 1 mM 5-[3H]deoxycytidine (NEN Life Sciences, Boston, MA; specific activity, 5,000 dpm/pmol) was added to the dishes, followed by incubation for 1 h at 37°C. Reactions were stopped with 100 ml of ice-cold 44% perchloric acid, and contents were mixed and incubated for 20 min at 4°C. The extract was then transferred to 2-ml microcentrifuge tubes containing 350 mg of 35 mesh activated charcoal, vortexed, and centrifuged for 10 min at 10,000 x g. Supernatant (350 µl) was mixed with 5 ml of Bio Safe II (Research Products International, Inc., Mount Prospect, IL), and radioactivity was quantified using a Beckman LS-6000 scintillation spectrophotometer. TS activity was calculated as pmol of 3H released/106 cells/min.
Measurement of Triphosphate Pools.
Cell extract preparation and the conditions for HPLC analysis of dNTP pool measurements were performed as described previously (20)
. The samples were analyzed using a Waters HPLC system (600E Multisolvent delivery system and controller, 490E Multiwavelength detector, 717 Autosampler, and Millenium chromatography manager software). Nucleotides were separated on a 4.6 x 250-mm Partisil-10 SAX column (Whatman). The mobile phase consisted of 0.35M NH4H2PO4 (pH 3.0) with H3PO4 at a flow rate of 2 ml/min. Peaks were detected at 254 nm. Retention time of dCTP, dTTP, dATP, and dGTP were 10.6, 12.4, 14.5, and 26.8 min, respectively. dNTPs were quantified by peak heights against authentic standards using the Millenium software. The percentage IdUrd DNA incorporation was calculated as follows: [(IdUrd)/[(dThd) + (IdUrd)]] x 100.
|
Results |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
; 0.3–30 µM), and IdUrd (Fig. 2B
; 1–10 µM) are shown in Fig. 2
. As reported previously (8
, 11
, 13)
, the HCT116/3-6 cells showed 1 log lower survival after exposure to 0.1 and 1.0 µM 6-TG compared to the parental HCT116 cells. In contrast, HCT116/3-6 cells showed little cytotoxicity (<<1 log cell kill) after the 18-h exposure to 1–10 µM IdUrd and also have a consistently higher survival compared to parental HCT116 cells. Comparable survival data were found for the HCT116 and HCT116/3-6 cells after exposure to BrdUrd as well (data not shown). Clonogenic survival after the three separate drug treatments (6-TG, IdUrd, and BrdUrd) is similar in HCT116 and HCT116/2-1 cells, which are both hMLH1- (data not shown).
|
, we present our data evaluating the percentage of dThd replacement by IdUrd after an 18-h exposure to 1–10 µM IdUrd. The hMLH1 corrected subclone (HCT116/3-6) shows a 2–3-fold lower level of dThd analogue in DNA after IdUrd exposure than HCT116 cells. There was a 1.5–2.0-fold lower level of BrdUrd in HCT116/3-6 cells than in HCT116 cells, similar to the data for IdUrd. For example, after exposure to a clinically relevant dose of 2 µM BrdUrd, HCT116/3-6 cells and HCT116 cells showed 4.8 ± 0.1% and 8.6 ± 0.1% incorporation levels, respectively. As a control, the percentage of dThd DNA incorporation values were the same in HCT116 and HCT116/2-1 cells after IdUrd and BrdUrd exposures (data not shown). Additionally, MC5 (Mlh1+/+) spontaneously immortalized MEF cells show lower levels of IdUrd present in their DNA than MC3 (Mlh1-/-) MEF cells derived from Mlh1 knockout mice (Fig. 3B)
, supporting our results using the human colon carcinoma cells.
|
. An intermediate effect (SER = 1.32) on radiation survival was noted with a preirradiation exposure to 5 µM BrdUrd. Again, no differences in radiation survival (± preirradiation exposures to IdUrd/BrdUrd) were found in the HCT116/2-1 cells compared to parental HCT116 cells (data not shown).
|
, we measured the enzyme activities of TK and TS in exponentially growing cell populations. Both TK and TS enzyme activities were modestly higher in HCT116/3-6 cells compared to HCT116 cells (Fig. 5A)
. The TK levels were 1.991 ± 0.002 and 1.548 ± 0.003 pmol TMP/106 cells/min in cytosolic extracts, whereas the TS activity levels in intact cells were 0.304 ± 0.005 and 0.208 ± 0.003 pmol of 3H released/106 cells/min for HCT116/3-6 cells and HCT116 cells, respectively. Furthermore, measurements of TS activity in these two genetically matched cell populations showed only a modest inhibition (10–30%) after an 18-h exposure to 5 µM IdUrd or BrdUrd compared to a marked (90%) inhibition after a 2-h exposure to 5 µM FdUrd, which is known to be a strong inhibitor of TS (Fig, 5A)
. TK and TS enzyme activities were similar in the two hMLH1- cell lines, HCT116 and HCT116/2-1 (data not shown).
|
, showing slightly higher levels overall in the HCT116/3-6 cells (hMLH1+). These higher dNTP levels in HCT116/3-6 cells correlate with the slightly higher, measured enzyme activities of TK and TS (Fig. 5A)
. |
Discussion |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
These results were somewhat surprising because the dThd analogues would not be expected to result in the formation of mismatches upon their incorporation into DNA. Because the halogen atom in the dThd analogues has been substituted at the 5 position of the pyrimidine ring, the dThd analogues do not vary from normal dThd in their ability to form hydrogen bonds (Fig. 1A)
. However, it has been shown that mispairs can be generated during replication across DNA containing halogenated dThd analogues (21)
. It is therefore interesting to speculate whether the MMR system recognizes the analogues or distortions in DNA resulting from their initial incorporation or whether it recognizes mispairs generated during subsequent rounds of DNA replication. Current data from studies on the role of MMR in recognition and the cytotoxicity of chemically induced adducts in DNA, as well as the tolerance of MMR-deficient cells for alkylating agents, have supported a model that favors the latter hypothesis (22)
. After interaction of various alkylating agents such as MNNG, methylnitrosourea, and the antimetabolite 6-TG with DNA, cells undergo replication, and mispairing may result from the adducts in DNA. The resulting mispairs are then thought to be recognized by the MMR proteins, leading to futile cycles of DNA repair in the newly replicated strand. This futile cycling is hypothesized to ultimately result in cellular cytotoxicity.
However, we found substantial differences in the level of IdUrd and BrdUrd within the DNA of hMLH1+ cells compared to that of hMLH1- cells after only 1 population doubling, indicating that the MMR machinery recognizes the analogues or distortions in DNA introduced upon initial halogenated dThd analogue incorporation. Both mismatched bp arising during normal cellular processes and the halogenated dThd analogues appear to be removed from DNA by the MMR system without significant cytotoxicity. However, other adducts such as those induced by 6-TG and cisplatin, which are recognized by the MMR system, appear to result in significant cellular cytotoxicity. Consequently, there may be structural differences in these types of adducts that determine whether the MMR machinery will recognize and remove the adduct or take part in a cascade that ultimately results in cytotoxicity. Structural studies have been done on different naturally occurring mispairs in a B-DNA undecamer, and a correlation was found between helical distortion caused by mispairs and the efficacy of MMR (23) . Bases involved in G-T and A-C mismatches, which are repaired most efficiently by the MMR system, are displaced into the major and minor grooves but remain an integral part of the helix rather than looping out from the helix. However, in the case of A-G and C-T mismatches, which are repaired at much lower frequencies by MMR (23) , the bases involved in the mispair loop out from the helix. These data suggest that differences in structural alterations in DNA resulting from mispairs may account for the varying efficacy of MMR. It has also been shown that single bp mismatches are recognized by a different complex of MMR proteins than mispairs in small insertion/deletion loops (24) , indicating that structural differences dictate which MMR proteins are involved in recognition. Given the different responses by MMR-proficient cells to single base mismatches and incorporated halogenated pyrimidines compared to agents such as MNNG, 6-TG, and cisplatin, it also seems possible that structural differences may account for the type of response elicited by the MMR system.
The fact that the DNA levels of halogenated pyrimidines appear to remain higher in MMR-deficient tumor cells may have clinical relevance as well. MMR deficiency, due to mutations in one of the known MMR genes, is associated with hereditary nonpolyposis colorectal cancer, which has been reported to account for up to 10% of total colorectal cancer and some spontaneous cases of colon cancer as well. Recently, methylation of the hMLH1 promoter resulting in a lack of hMLH1 protein expression has been found in a number of microsatellite-unstable spontaneous colon cancers as well (25 , 26) . This demonstrates another method of inactivation of MMR, which appears to be a more common occurrence in spontaneous colon cancer, and underscores the importance of MMR deficiency in both spontaneous and hereditary colorectal cancer. MMR-deficient cells have been shown to be relatively resistant to a large number of chemotherapeutic drugs including temozolomide (10 , 15) , Adriamycin (14) , procarbazine (15) , busulfan (15) , etoposide (11) , cisplatin (11 , 14) , carboplatin (11) , mercaptopurine (12) , and 6-TG (11, 12, 13 , 23) . Thus far, no drugs have been reported to selectively target MMR-deficient cells. However, our data indicate that MMR-deficient cells may respond to a combined treatment of halogenated dThd analogues followed by IR.
In summary, the 5-substituted halogenated pyrimidine analogues appear to be removed from the DNA of MMR-proficient cells, resulting in low levels of cytotoxicity and a lower level of radiosensitization by exposure to IdUrd or BrdUrd than MMR-deficient cells. In accordance with these data, MMR-deficient cells, which display higher levels of incorporated analogues, show a corresponding increase in radiation sensitivity after analogue treatment. Consequently, whereas it is possible to increase the radiosensitivity of cells containing a proficient MMR system by pretreatment with IdUrd or BrdUrd, a deficiency in this repair process can result in even greater radiosensitization by these halogenated dThd analogues. These results are interesting because they not only suggest a means of selectively eliminating cells that have lost their ability to perform DNA MMR but may also indicate that the type of adduct or distortion induced in DNA by various chemotherapeutic agents dictates whether the MMR system will participate in a cytotoxic cascade after recognition or will successfully remove the lesion.
|
FOOTNOTES |
|---|
1 Supported in part by NIH Grants CA-50595 and CA-79782. 
2 To whom requests for reprints should be addressed, at the Department of Radiation Oncology, Case Western Reserve University, Lerner B-181, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106-5056. Phone: (216) 844-2530; Fax: (216) 844-4799.
3 The abbreviations used are: dThd, thymidine; MMR, mismatch repair; 6-TG, 6-thioguanine; BrdUrd, bromodeoxyuridine; IdUrd, iododeoxyuridine; TK, dThd kinase; TS, thymidylate synthase; IR, ionizing radiation; HPLC, high-performance liquid chromatography; FdUrd, fluorodeoxyuridine; MEF, mouse embryonic fibroblast; SER, sensitizer enhancement ratio; MNNG, N-methyl-N'-nitro-N-nitrosoguanidine; dNTP, deoxynucleotide triphosphate.
Received 12/23/98. Accepted 3/ 3/99.
|
REFERENCES |
|---|
|
TopABSTRACTIntroductionMaterials and MethodsResultsDiscussionREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  E. Gurkan, J. E. Schupp, M. A. Aziz, T. J. Kinsella, and K. A. Loparo Probabilistic Modeling of DNA Mismatch Repair Effects on Cell Cycle Dynamics and Iododeoxyuridine-DNA Incorporation Cancer Res., November 15, 2007; 67(22): 10993 - 11000. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Shewach and T. S. Lawrence Antimetabolite Radiosensitizers J. Clin. Oncol., September 10, 2007; 25(26): 4043 - 4050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yamane, J. E. Schupp, and T. J. Kinsella BRCA1 Activates a G2-M Cell Cycle Checkpoint following 6-Thioguanine-Induced DNA Mismatch Damage Cancer Res., July 1, 2007; 67(13): 6286 - 6292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Flanagan, B. W. Robinson, C. M. Krokosky, and D. S. Shewach Mismatched nucleotides as the lesions responsible for radiosensitization with gemcitabine: a new paradigm for antimetabolite radiosensitizers Mol. Cancer Ther., June 1, 2007; 6(6): 1858 - 1868. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Kim, L. H. Colangelo, H. S. Wieand, S. Paik, I. R. Kirsch, N. Wolmark, and C. J. Allegra Prognostic and Predictive Roles of High-Degree Microsatellite Instability in Colon Cancer: A National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study J. Clin. Oncol., March 1, 2007; 25(7): 767 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Seo, T. Yan, J. E. Schupp, K. Yamane, T. Radivoyevitch, and T. J. Kinsella The Interaction between Two Radiosensitizers: 5-Iododeoxyuridine and Caffeine Cancer Res., January 1, 2006; 66(1): 490 - 498. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Seo, T. Yan, J. E. Schupp, V. Colussi, K. L. Taylor, and T. J. Kinsella Differential Radiosensitization in DNA Mismatch Repair-Proficient and -Deficient Human Colon Cancer Xenografts with 5-Iodo-2-pyrimidinone-2'-deoxyribose Clin. Cancer Res., November 15, 2004; 10(22): 7520 - 7528. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. W. Robinson, M. M. Im, M. Ljungman, F. Praz, and D. S. Shewach Enhanced Radiosensitization with Gemcitabine in Mismatch Repair-Deficient HCT116 Cells Cancer Res., October 15, 2003; 63(20): 6935 - 6941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Berry, T. Loh, T. Yan, and T. J. Kinsella Role of MutS{alpha} in the Recognition of Iododeoxyuridine in DNA Cancer Res., September 1, 2003; 63(17): 5490 - 5495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Taverna, H.-s. Hwang, J. E. Schupp, T. Radivoyevitch, N. N. Session, G. Reddy, D. A. Zarling, and T. J. Kinsella Inhibition of Base Excision Repair Potentiates Iododeoxyuridine-induced Cytotoxicity and Radiosensitization Cancer Res., February 15, 2003; 63(4): 838 - 846. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Berry, T. W. Davis, J. E. Schupp, H.-S. Hwang, Niels de Wind, and T. J. Kinsella Selective Radiosensitization of Drug-resistant MutS Homologue-2 (MSH2) Mismatch Repair-deficient Cells by Halogenated Thymidine (dThd) Analogues: Msh2 Mediates dThd Analogue DNA Levels and the Differential Cytotoxicity and Cell Cycle Effects of the dThd Analogues and 6-Thioguanine Cancer Res., October 1, 2000; 60(20): 5773 - 5780. [Abstract] [Full Text]
|
|
|
|
|
|
T. J. Kinsella, J. E. Schupp, T. W. Davis, S. E. Berry, H.-S. Hwang, K. Warren, F. Balis, J. Barnett, and H. Sands Preclinical Study of the Systemic Toxicity and Pharmacokinetics of 5-Iodo-2-deoxypyrimidinone-2'-deoxyribose as a Radiosensitizing Prodrug in Two, Non-Rodent Animal Species: Implications for Phase I Study Design Clin. Cancer Res., September 1, 2000; 6(9): 3670 - 3679. [Abstract] [Full Text]
|
|
|
|
|
|
T. J. Kinsella, K. A. Vielhuber, K. A. Kunugi, J. Schupp, T. W. Davis, and H. Sands Preclinical Toxicity and Efficacy Study of a 14-day Schedule of Oral 5-Iodo-2-pyrimidinone-2'-deoxyribose as a Prodrug for 5-Iodo-2'-deoxyuridine Radiosensitization in U251 Human Glioblastoma Xenografts Clin. Cancer Res., April 1, 2000; 6(4): 1468 - 1475. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
