SEARCH · PubMed Health
Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
The radiosensitivity of DNA in human cervix carcinoma was examined by using alkaline sucrose gradient centrifugation to measure radiation-induced single-strand breaks. The DNA strand-break efficiencies observed in DNA of 18 specimens fell into two distinct groups, radiosensitive and radioresistant. The difference in DNA radiosensitivity may be correlated with the pathological classifications of the carcinomas.
Using cultured HeLa S3 cells, the radiosensitizing and cytotoxic effects of newly synthesized derivatives of dinitroimidazole were investigated and compared with those of misonidazole. 2,4-Dinitroimidazole-1-ethanol radiosensitized hypoxic cells selectively. At 5 mM misonidazole, the enhancement ratio was 1.95; with 0.5 mM 2,4-dinitroimidazole-1-ethanol, almost the same enhancement could be obtained. This indicates that the radiosensitizing effect of the latter agent was about 10 times greater than that of misonidazole. However, its cytotoxicity was twice that of misonidazole under hypoxic conditions and there was no apparent differential cytotoxicity to hypoxic and aerobic cells.
The comparative pharmacokinetics of various nitroimidazole radiosensitizers in different species are reviewed. Radiosensitization is dependent upon the tumor concentration at the time of radiotherapy, whereas host toxicity, including peripheral neuropathy, appears to be related to the tissue exposure or area under the curve (AUC). In contrast to in vitro structure-activity relationships, lipophilicity has a major effect on therapeutic ratio by influencing pharmacokinetics. Nitroimidazoles penetrate lipoid membranes by passive diffusion, the rate increasing with lipophilicity. Derivatives more hydrophilic than misonidazole (e.g., Ro 05-9963, SR-2508, and SR-2555) penetrate nervous tissues comparatively slowly, the corresponding AUC's are lower and they are generally less toxic. They are eliminated mainly by renal clearance, and also have shorter plasma t1/2's than misonidazole in the dog, but not in the mouse. The more lipophilic drugs are eliminated mainly by metabolism and their t1/2's are reduced by hepatic enzyme induction. Ro 07-0913, more lipophilic than misonidazole, has a shorter t1/2 in the mouse through more rapid metabolism to Ro 05-9963. Tumor penetration is independent of t1/2, at least over the range 1/2-20 hours, and also independent of partition coefficient over the range 0.026 to at least 1.5. The therapeutic ratio may be increased with drugs both more and less lipophilic than misonidazole. Most plasma data for intravenous radiosensitizers can be described by a two-compartment open model. But in the mouse, the kinetics of misonidazole are dose dependent with increasing apparent t1/2 and AUC at higher doses due to saturable Michaelis-Menten kinetics for metabolism.
Gemcitabine is a novel nucleoside analog that has shown clinical activity in a variety of solid tumors. The use of gemcitabine in combination with radiation was investigated in vitro using HT-29 colon carcinoma cells. Gemcitabine was demonstrated to be a potent radiosensitizer even at noncytotoxic concentrations. Increasing the concentration of gemcitabine and/or the duration of exposure increased the radiosensitization of cells. Biochemical studies indicated that a reduction in the dATP pool was the most likely mechanism of radiosensitization by gemcitabine. This effect is of great clinical importance and should be investigated in vivo.
Recovery from the lethal effects of irradiation is commonly found when cultured mammalian cells are irradiated at low dose rates when compared to the same cells irradiated at higher dose rates. However, this cellular recovery process is severely reduced or absent in a number of radiosensitive cell lines, including those derived from the human disorder ataxia telangiectasia (AT). The genetic and molecular basis of such recovery processes is not understood, despite their importance. The responses of cells of three further radiosensitive lines, irs1, irs2 and irs3, shown previously to be mutated in different genes, to low-dose-rate radiation are now presented. Plateau-phase cultures of cells of the irs2 line were found to have little or no cellular recovery, while irs1 and irs3 had considerable recovery potential. In comparing the known properties of the radiosensitive lines lacking cellular recovery, including xrs, XR-1 and scid as well as AT and irs2, it is argued that the gene products lacking in these lines normally act coordinately in a specific damage-recognition pathway. The recovery pathway is likely to be associated with the rejoining of DNA double-strand breaks, since several of these recovery-defective lines have a measurable deficiency in break repair.
Lack of DNA-dependent protein kinase (DNA-PK) activity confers radiosensitivity and defective DNA double-strand break repair. Nine human malignant glioma cell lines were studied to determine whether differences in DNA-PK activity reflect differences in inherent radiosensitivity or are predictive of tumor treatment response. DNA-PK activity was present in all cell extracts, as were the DNA-PK proteins, DNA-PK catalytic subunit, Ku p70, and Ku p80. No correlation was found between the levels of DNA-PK activity and inherent radiosensitivity or in the tumor treatment response. These preliminary results suggest that variation in DNA-PK activity may not be a determinant of clinical response in malignant glioma.
Electron-affinic compounds with strong DNA intercalating properties have demonstrated less than the expected radiosensitization due to restriction of their mobility along the DNA backbone and their lower extravascular diffusion in tumors. A 2-nitroimidazole linked 1,2,3,4-tetrahydroacridine derivative (THNLA-1) has been synthesized as a hypoxia-selective cytotoxin and radiosensitizer with presumably lower DNA-binding affinity due to the perturbation of the planarity in the acridine ring. THNLA-1 is a good hypoxia-selective cytotoxin with a differential toxicity of approximately equal to 11 in V79 cells, but it is approximately equal to 2 times less potent on a concentration basis than NLA-1 (the 2-nitroimidazole linked acridine analog). However, THNLA-1 is a very efficient radiosensitizer, showing a sensitization enhancement ratio (SER) of 3.04 +/- 0.05 at 100 microM at 25 degrees C, and the concentration giving an SER of 1.6(C1.6) is 19.0 +/- 0.5 microM. The therapeutic index, defined as the ratio of the clonogenic IC50 under aerobic conditions for 1-h exposure (IC50A,1h) to the C1.6 value, is 20 for THNLA-1 vs. 11 for NLA-1. THNLA-1's partition coefficient in octanol/water is 0.14 +/- 0.02. Topoisomerase I and II interaction studies with THNLA-1 showed that topoisomerase I-mediated relaxation of supercoiled DNA was inhibited at relatively high THNLA-1 concentrations (> or = 1000 microM), while topoisomerase II-mediated decatenation of kinetoplast DNA remained unaffected even in concentrations toxic in vitro under aerobic conditions. Uptake studies under aerobic conditions showed high intracellular drug concentrations, compatible with the required ones for topoisomerase I inhibition.
Most drug discovery efforts have focused on finding new DNA-damaging agents to kill tumor cells preferentially. An alternative approach is to find ways to increase tumor-specific killing by modifying tumor-specific responses to that damage. In this report, we ask whether cells lacking the G1-S arrest in response to X-rays are more sensitive to X-ray damage when treated with agents that override G2-M arrest. Mouse embryonic fibroblasts genetically matched to be (+) or (-) p53 and rat embryonic fibroblasts (+) or (-) for wild-type p53 function were irradiated with and without caffeine, a known checkpoint inhibitor. At low doses (500 microM), caffeine caused selective radiosensitization in the p53(-) cells. At this low dose (where no effect was seen in p53(+) cells), the p53(-) cells showed a 50% reduction in the size of the G2-M arrest. At higher doses (2 mM caffeine), where sensitization was seen in both p53(+) and p53(-) cells, the radiosensitization and the G2-M override were more pronounced in the p53(-) cells. The greater caffeine-induced radiosensitization in p53(-) cells suggests that p53, already shown to control the G1-S checkpoint, may also influence aspects of G2-M arrest. These data indicate an opportunity for therapeutic gain by combining DNA-damaging agents with compounds that disrupt G2-M arrest in tumors lacking functional p53.
To assess the role of expression of the retinoblastoma (RB) gene on the sensitivity of cells to the cytotoxic effects of ionizing radiation, we transfected a normal RB gene into cells of RB+ and RB- osteosarcoma cell lines and an RB- prostate carcinoma line and studied the radiosensitivity of the cells before and after transfection. Four transfected clones were isolated from the two RB- tumor cell lines that expressed the product of the transfected normal RB gene and contained no mutations in the pocket and C-terminal regions by sequencing. A small increase in radiosensitivity was observed in cell lines transfected with the pDOL plasmid vector alone, containing the neo gene and a long terminal repeat (LTR) promoter. However, no significant change in radiosensitivity occurred in transfected cells expressing the normal RB gene compared to controls transfected with an RB- plasmid. Based on this and other information, we conclude that RB gene function is not involved in the response of these human tumor cells to the cytotoxic effects of radiation.
The effect of caffeine, the methylated xanthine, in sensitizing the lethal action of ionizing radiation in vitro was investigated in human cancer cells which were clinically known to be radioincurable. The tumor lines were hepatocellular carcinoma and colon adenocarcinoma. Plateau phase cultures, after absorbing doses of 2 Gy, survived at a rate of 56.30 per cent for colon cancer and at 66.05 per cent for liver cancer. Both lines were radiosensitized by caffeine but at different potencies. Noteworthily, hepatocellular carcinoma whilst less radiosensitive than colon adenocarcinoma was 4 times more susceptible to caffeine. The lowest effective caffeine concentration for liver cancer was 2 mM which slightly exceeded the anticipated lethal concentration in humans. Research on radiosensitizing effect of methylated xanthines on hepatoma system still remains intriguing. Future work should be pursued with the use of less toxic compounds, such as theobromine.
The response to low doses of X rays was assessed in cells of three hamster cell lines which are defective in DNA repair and was compared with their parental lines. Cells of the V79-derived double-strand break repair-deficient line XR-V15B showed no radioresistance in the 0.5-Gy range compared with the V79B wild type, but instead showed an exponential response. Cells of the single-strand break repair-deficient line EM9 showed hyper-radiosensitivity and exhibited increased radioresistance. Most interestingly, cells of the UV-20 cell line appeared to respond exponentially, as a continuation of the hyper-radiosensitive portion of the curve, with no evidence of increased radioresistance. This line is defective in an incision step of excision repair and is sensitive to crosslinking agents. Further studies are warranted to address the possible role of single- and double-strand break repair and excision repair in hyper-radiosensitivity and increased radioresistance.
The assessment of drugs designed to be useful in the eradication of hypoxic (resistant) cells involves comparison of hypoxic and aerobic radiosensitization, cytotoxicities, as well as DNA binding and reduction potentials. Three pairs of isomers of quinoline complexes [amino dichloro quinoline platinum (II)] were studied in this context. For the cis 5- and 6-nitroquinoline complexes, the DNA binding and toxicity were higher with the 5-substituted ligand. Reduction potentials were similar (-260 and -280 mV). No selectivity for hypoxic toxicity was observed, but radiosensitizing ability by both complexes was greater in hypoxic (than oxic) Chinese hamster ovary (CHO) cells. The trans 5-nitroquinoline complex produced better sensitization in hypoxia than its cis isomer [enhancement ratio (ER) 1.7 at 10 microM versus 40 microM for cis]. However, this was accompanied by some aerobic sensitization. The trans isomer of the (unsubstituted) quinoline complex was considerably more toxic than its cis isomer. Neither showed selectivity for hypoxia, either as radiosensitizers or as cytotoxins, which may be attributable to the lack of a reducible (nitro) function. Four quinoline complexes showed high activity in cisplatin-resistant L1210 cells, with the lowest resistance factor being for the trans quinoline complex. Results suggest that trans complexes with one aromatic ring may have activity different from the cis geometry, which should be exploited with respect to cisplatin resistance and cross-resistance with radiation.
The free radical mechanism of enhancing radiosensibility by the Synergic Recipe to Strengthen Body Resistance (SRSBR) consisting of 10 Chinese drugs was studied by electron spin resonance (ESR) with spin trapping reagent--Nitroso-tert-butane (NtB) following irradiation of the Deoxy thymidine (dT) solution system by 60Co 3.7 PBq. The results showed SRSBR cannot only enhance the generation of e- aq but also enhance the production of . OH and H . after irradiation with gamma ray in dT-NtB-SRSBR aqueous solution system. These result in damage to biological molecules, attacking and killing tumor cells radiosensitized by SRSBR. The characteristics of SRSBR for radiosensitization are concluded to be increasing production of . OH and H. in comparison with the well-known radiosensitizer-Misonidazole (Miso).
Cell intrinsic radiosensitivity is of great importance in radiation therapy, but its molecular basis is still uncertain. Since DNA double strand breakage is considered to be the most important lesion related to cell death induced by ionizing radiation, the relationship between DNA double-strand breakage, repair and cell survival was investigated in three cell lines: Chinese hamster cell (CHO-K1), human fibroblast and human renal carcinoma (Tu 25). The D0 values after X-irradiation were 1.73, 1.23, and 0.89 Gy, respectively, showing that Tu 25 was the most sensitive among them. DNA double-strand breaks were measured by CHEF electrophoresis, the initial yield of double-strand break per dose in the three cell lines was almost the same, and no correlation to cell survival was found. However, the rejoining capacity for DNA double-strand break differed. After a dose of 20 Gy, the repair rate was markedly lower in Tu 25, with a half repair time of 40 min, as compared with the other two cell lines with half repair times of 15 min. The results strongly supported the correlation between the repair capacity for DNA double-strand break and cell survival. It was concluded that DNA repair capacity is one of the determinants of cell radiosensitivity. Estimation of DNA double-strand break rejoining by CHEF was suggested as a predictive assay for radiosensitivity of human tumor cells.
Korbelik and Skov (Radiat. Res. 119, 145-156, 1989) have reported that cis-diamminedichloroplatinum (II) (cisplatin) shows substantial preferential radiosensitization of hypoxic cells in vitro at low radiation doses (1-4 Gy), and that the interaction seen with low doses of radiation is greatly diminished at high radiation doses. If such an interaction occurred with fractionated irradiation in vivo, it would be extremely important to radiation therapy, since the sensitizer enhancement ratios achievable in the low-dose region are higher than those achievable with current hypoxic cell radiosensitizers. We have tested this possibility in an experimental mouse tumor using fractionated irradiation under conditions in which the response of the tumor was determined by either its aerobic or its hypoxic cells. RIF-1 tumors were irradiated with 10 fractions of 1-4 Gy every 12 h with cisplatin given either as 12 mg/kg once before the first radiation dose or as 1.2 mg/kg at various times prior to each radiation dose. The tumors were irradiated with or without a clamp applied 2-3 min before each radiation dose. The effectiveness of the treatments was assayed by regrowth delay. Cisplatin caused a similar regrowth delay when used alone in both clamped and nonclamped tumors and produced a similar additive or supra-additive interaction when used with the 10 fractionated radiation schedule whether the tumors were hypoxic or aerobic. Our data suggest that cisplatin does not show any preferential radiosensitization of hypoxic cells with low-dose multifraction irradiation in this tumor, although a clear schedule-dependent interaction between the drug and radiation was seen for both aerobic and hypoxic tumors.
Many tumor cells have a greater resistance to ionizing radiation than their normal counterparts, suggesting that the development of drugs that can reduce that radioresistance would potentiate the efficacy of radiation therapy. Because activated H-ras expression has been shown to markedly increase radiation resistance in some transformed cells, the inactivation of H-ras would then be predicted to radiosensitize these tumor cells, while leaving normal cells unaffected. H-ras depends for activity upon farnesylation, which can be blocked by farnesylation inhibitors, including the compound FTI-277. In keeping with this prediction, inhibition of H-ras processing using FTI-277 resulted in higher levels of apoptosis after irradiation and increased radiosensitivity in H-ras-transformed rat embryo cells but did not affect control cells. These experiments suggest that farnesylation inhibitors may prove clinically useful as radiosensitizers of tumors that depend on ras function.
BACKGROUND: Preoperative radiation therapy followed by radical cystectomy for invasive bladder cancer has been considered beneficial for selected patients whose tumors display a pronounced initial response to radiotherapy. METHODS: In order to determine whether overexpression of p53 gene products or proliferating cell nuclear antigen (PCNA) can be used to predict the response of invasive bladder cancer to radiotherapy, an immunohistochemical study of bladder cancers with monoclonal antibodies to p53 or PCNA (PAb 1801 or PC10) was performed. The results of immunostaining of pretreatment biopsy specimens from 60 invasive bladder cancers were analyzed to determine the relationship between labeling for p53 or PCNA and radiosensitivity as determined by histopathological examination of cystectomy specimens obtained after preoperative radiation. RESULTS: The group with a good response to preoperative radiation therapy had better progression-free rates than did the group with a poor response (P < 0.05). There was no significant difference in radiosensitivity between patients with primary tumors with negative and positive immunostaining for p53. On the other hand, the PCNA labeling index (LI) differed significantly between tumors with poor and good histopathological responses to radiation therapy (P < 0.05). CONCLUSION: No correlation was found between immunohistochemically detectable alterations of p53 gene products and the radiosensitivity of invasive transitional cell carcinoma of the bladder. However, PCNA immunostaining may be useful for identifying patients for whom preoperative radiation might prove beneficial.
Gemcitabine has high clinical activity in several solid tumors that are treated with radiotherapy and/or chemotherapy. The mode of action of gemcitabine involves a number of intracellular changes that are shared by other radiation sensitizing anticancer drugs. There is therefore a clear rationale for investigating the interaction between gemcitabine and radiation in human cancer cell lines in vitro. Gemcitabine has been shown to be a potent radiosensitizer in human colorectal, pancreatic, and other solid tumor cell lines. Gemcitabine produces radiation enhancement ratios that are higher than those of other established radio-sensitizing agents, and this radiation enhancement occurs at low noncytotoxic concentrations. Radiosensitization increases with dose and with duration of exposure to gemcitabine, and is greatest when exposure to gemcitabine precedes radiation. The primary radiosensitizing effect of gemcitabine seems to be associated with depletion of endogenous nucleotide pools; deoxyadenosine triphosphate reduction is particularly striking, even at the lowest concentrations of gemcitabine. These studies suggest a number of approaches that are relevant to the clinical use of gemcitabine in patients with solid tumors.