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Results for “Radiosensitivity”

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At least 505 records · Page 28Linked to original sources

PubMed2003

Spontaneous and radiation-induced apoptosis in colorectal carcinoma cells with different intrinsic radiosensitivities: survivin as a radioresistance factor.

BACKGROUND: Spontaneous apoptosis has been shown to predict tumor response to radiochemotherapy in rectal cancer in vivo. It remains to be elucidated, however, which genetic profile determines whether a tumor is more or less prone to apoptosis. Recently, a novel member of the inhibitor of apoptosis protein family, designated survivin, was identified. We investigated the impact of survivin expression on tumor cell apoptosis in three colorectal cell lines of different intrinsic radiosensitivities. METHODS AND MATERIALS: Survivin protein expression was measured by Western blot analysis, and survivin mRNA expression by quantitative TaqMan reverse transcription polymerase chain reaction, both in untreated cell and after irradiation with 2 and 8 Gy. The expression profile was then correlated to spontaneous and radiation-induced apoptosis (Tunel-Assay, DAPI-staining) in three colorectal cell lines of low (SW 480), intermediate (HCT-15), and high radiosensitivity (SW 48), as determined by the colony-forming assay. RESULTS: In vitro analysis revealed higher spontaneous and higher radiation-induced apoptosis rates in the radiosensitive line (SW 48), as compared with the more resistant line (SW 480). In Western blot analysis and in TaqMan analysis, SW 480 was characterized by a higher spontaneous expression and a pronounced induction of survivin 48 h after irradiation, whereas survivin expression was low when untreated and not increased after irradiation in the most radiosensitive line SW 48. HCT-15 was intermediate, both with respect to the level of survivin mRNA and protein expression. CONCLUSION: The inverse correlation of survivin-expression with spontaneous and radiation-induced apoptosis suggests that survivin is an important inhibitor of apoptosis in colorectal cancer cell lines. Analysis of survivin mRNA or protein expression may therefore provide predictive information on radio- and chemoresistance of individual colorectal tumors.

Adenocarcinoma↗

PubMed2003

Erythropoietin restores the anemia-induced reduction in radiosensitivity of experimental human tumors in nude mice.

PURPOSE: The effect of recombinant human erythropoietin (rhEPO) on the radiosensitivity of human tumor xenografts growing in anemic and nonanemic nude mice was studied. METHODS AND MATERIALS: Anemia was induced by total body irradiation ([TBI], 2 x 4 Gy) of mice before tumor implantation into the subcutis of the hind leg. The development of anemia was prevented by rhEPO (750 U/kg s.c.) given 3 times weekly starting 2 weeks before TBI. Fourteen days after fractionated TBI (tumor volume of approx. 40 mm(3)), single-dose irradiation of the tumor with varying doses was performed so that in full dose-response relationship for the probability of tumor cure was obtained. RESULTS: Radiation-induced anemia (hemoglobin concentration [cHb] = 9.9 g/dl) led to a reduced radiosensitivity compared to controls [49.4 vs. 40.1 Gy radiation dose to control 50% of the tumors (TCD50)]. Upon rhEPO treatment for anemia prevention (cHb = 13.3 g/dl), the TCD50 was 39.8 Gy, illustrating restored radiosensitivity compared to anemic mice. CONCLUSION: These data provide further experimental evidence for restored radiosensitivity upon prevention of anemia with rhEPO.

Anemia↗

PubMed2003

Radiosensitization by pemetrexed of human colon carcinoma cells in different cell cycle phases.

PURPOSE: The novel folate antimetabolite Alimta (pemetrexed disodium, LY231514) exhibits antitumor activity in a broad array of human malignancies and was recently found to enhance radiation-induced cell killing in vitro. In the present study, a possible cell cycle phase-specific radiosensitization by pemetrexed was assessed. METHODS AND MATERIALS: Widr human colon carcinoma cells were synchronized by serum withdrawal/stimulation that yielded about 80% cells with G1 DNA content 6 h after replating and more than 60% S-phase cells after 22 h, as assessed by flow cytometry. The respective cultures were irradiated with doses up to 12 Gy in combination with a subtoxic pemetrexed exposure (1.06 microM for 2 h: about 80% survival), or after mock treatment. Survival curves were generated by the clonogenic assay; apoptosis was measured by sub-G1 DNA flow cytometry. RESULTS: The combination treatment of the G1 cells and of the more radioresistant S-phase cell preparations yielded survival rates that were lower than expected for independent cell killing. Radiosensitization, calculated as the ratio of the mean inactivation doses without or with drug exposure (enhancement ratio), was not significantly different for the two cell preparations (enhancement ratio of 2.1 and 2.3, respectively) and was similar to the previously reported value for log-phase cells. Pemetrexed exposure was unable to stimulate an apoptotic response of these cells to radiation. CONCLUSIONS: Radiosensitization by pemetrexed is not cell cycle phase-specific, and the relative radioresistance of S-phase cells is retained. Apoptosis seems to have no influence on radiosensitization in this cell line.

Apoptosis↗

PubMed1996

Preferential radiosensitization of G1 checkpoint-deficient cells by methylxanthines.

PURPOSE: To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53. METHODS AND MATERIALS: A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation. RESULTS: Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans. CONCLUSION: This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues.

Cell Survival↗

PubMed1997

The merits of cell kinetic parameters for the assessment of intrinsic cellular radiosensitivity to photon and high linear energy transfer neutron irradiation.

PURPOSE: Differences in tumor response and intrinsic cellular radiosensitivity make the selection of patients for specific radiation modalities very difficult. The reasons for these differences are still unclear, but are thought to be due to genomic and cellular characteristics. Because radiosensitivities vary between cell cycle stages and because S phase cells are very radioresistant, cell cycle kinetic parameters could be a candidate for predicting intrinsic radiosensitivity. METHODS AND MATERIALS: A panel of 15 tumor cell lines was analyzed for S phase content and potential doubling times (Tpot), and the influence of these parameters on the intrinsic radiosensitivity to 60Co gamma- and p(66)/Be neutron irradiation was assessed. RESULTS: S phase content and Tpot show a statistically significant correlation with the mean inactivation dose for photons. The correlation between cell kinetic parameters and the mean inactivation dose for neutrons showed the same trend as photon sensitivity but this was not found to be statistically significant. CONCLUSIONS: S phase content and Tpot were identified as suitable criteria for predicting photon sensitivity. It is suggested that cell kinetic parameters could play a role in identifying neutron sensitive tumors if both tumor and normal cells are analyzed.

Cobalt Radioisotopes↗

PubMed1998

The effect of activation of wild-type p53 function on fluoropyrimidine-mediated radiosensitization.

PURPOSE: We have hypothesized that fluoropyrimidine-mediated (FdUrd) radiosensitization occurs in cells that inappropriately enter S phase in the presence of drug, resulting in defective repair of radiation-induced DNA damage (14). This model would predict that prevention of entry into S phase would abrogate sensitization produced by FdUrd. We wished to test this prediction by blocking S phase entry of HT29 human colon cancer cells. METHODS: We used HT29 cells that had been transduced with a murine temperature-sensitive p53 (ts29G) and, as a control, HT29 cells transduced with a neomycin plasmid (HT29neo). The murine temperature-sensitive p53 demonstrates wild-type p53 function when cells are incubated at the permissive temperature (32 degrees C) and mutant p53 function at the nonpermissive temperature (38 degrees C). We determined the effect of wt p53 function on FdUrd-mediated radiosensitization and cell cycle progression. RESULTS: Incubation of ts29G cells at the permissive temperature (32 degrees C) activated p21 and blocked entry of cells into S phase. Whereas FdUrd greatly increased the radiosensitivity of HT29neo cells and ts29G cells incubated at 38 degrees C, FdUrd had no effect on the radiation sensitivity of ts29G cells incubated at the permissive temperature (32 degrees C). CONCLUSIONS: These findings are consistent with our hypothesis that FdUrd-mediated radiosensitization requires progression into S phase. It is possible that the heterogeneity of clinical responses seen after combined therapy with fluoropyrimidines and radiation is explained, in part, by differences among tumor cells in the control of S phase progression.

Antimetabolites, Antineoplastic↗

PubMed1999

Hematoporphyrin derivatives potentiate the radiosensitizing effects of 2-deoxy-D-glucose in cancer cells.

PURPOSE: Two deoxy-D-glucose (2-DG), an inhibitor of glucose transport and glycolysis, has been shown to differentially inhibit the repair of radiation damage in cancer cells by reducing the flow of metabolic energy. Since hematoporphyrin derivatives (Hpd) inhibit certain enzymes of the respiratory metabolism, resulting in an increase in the glucose usage and glycolysis, Hpd could possibly enhance the energy-linked radiosensitizing effects of 2-DG in cancer cells. The purpose of the present work was to verify this suggestion. METHODS AND MATERIALS: Two human tumor cell lines (cerebral glioma, BMG-1 and squamous cell carcinoma, 4197) and a murine tumor cell line (Ehrlich ascites tumor [EAT], F-15) in vitro were investigated. A commercially available preparation of Hpd, Photosan-3 (PS-3) was used in the present studies. Cells incubated with 0-10 microg/ml PS-3 for 0-24 h before irradiation were exposed to 2.5 Gy of Co-60 gamma rays and maintained under liquid holding conditions for 1-4 h to facilitate repair. 2-DG (0-5 mM) added at the time of irradiation was present during the liquid holding. Radiation-induced cytogenetic damage (micronuclei formation) and cell death (macrocolony assay) were analyzed as parameters of radiation response. Effects of these radiosensitizers on glucose usage and glycolysis were also studied by measuring the glucose consumption and lactate production using enzymatic assays. RESULTS: The glucose consumption and lactate production of BMG-1 cells (0.83 and 1.43 pmole/cell/h) were twofold higher than in the 4197 cells (0.38 and 0.63 pmole/cell/h). Presence of PS-3 (10 microg/ml) enhanced the rate of glycolysis (glucose consumption and lactate production) in these cells by 35% to 65%, which was reduced by 20% to 40% in the presence of 5 mM 2-DG. In exponentially growing BMG-1 and EAT cells, presence of 2-DG (5 mM; equimolar with glucose) for 4 hours after irradiation increased the radiation-induced micronuclei formation and cell death by nearly 40%, whereas no significant effects could be observed in 4197 cells. In EAT cells, radiation was also observed to induce apoptotic death, which was significantly increased in the presence of the combination (PS-3 + 2-DG). The combination (PS-3 + 2-DG) enhanced the radiation damage in all three cell systems by 60-100%. Furthermore, the radiosensitizing effects of the combination (PS-3 + 2-DG) were higher at pH 6.7 as compared to pH 7. 4. In the plateau phase, presence of 2-DG alone did not significantly influence the radiation response of either BMG-1 or of 4197 cells, whereas in combination with PS-3, 2-DG enhanced the radiation damage in both these cell lines by 40% to 50%. Furthermore, in BMG-1 cells, the effects of 2-DG were observed to be reversible to a very great extent, while that of the combination were mostly irreversible. CONCLUSION: The hematoporphyrin derivative PS-3 enhances the radiosensitizing effects of 2-DG in cancer cells, possibly by further reducing the energy supply leading to an irreversible inhibition of DNA repair, and increased cytogenetic damage and cell death. Since both these compounds have been used in clinical practice, further studies to investigate their use in improving radiotherapy of tumors are warranted.

Animals↗

PubMed1999

p53 mutation decreased radiosensitivity in rat yolk sac tumor cell lines.

PURPOSE: We reported that two established rat yolk sac tumor cell lines differ in their radiosensitivity by 1.7 fold, and the variation is most likely manifested by the differences seen in their apoptotic response. We investigated the relationship between radiosensitivity and p53 in these cell lines. METHODS AND MATERIALS: We assessed the status of p53 in cell lines by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and sequence analysis, and also analyzed protein expression of p53, p21, and bax as a function of time after irradiation to determine the signal transduction for p53 by immunoblotting. RESULTS: A band shift was observed only in exon 7 for the radioresistant NMT-1R cells and no band shift was detected for the radiosensitive NMT-1 cells. A band shift was confirmed also at the mRNA level. Exon 7 of p53 DNA showed a three base substitution of DNA at codon 267 to 268. Expression of p53, p21, and bax proteins in NMT-1R cells did not change after 10 Gy irradiation; however, in NMT-1 cells, the expression of these proteins was increased from 1-12 h after irradiation. CONCLUSION: A loss of p53 function by radiation-induced mutation of p53 decreased the radiosensitivity in these cell lines.

Animals↗

PubMed2000

Correlation between normal tissue complications and in vitro radiosensitivity of skin fibroblasts derived from radiotherapy patients treated for variety of tumors.

PURPOSE: To assess the relationship between fibroblast intrinsic radiosensitivity in vitro and late reactions of normal tissues in patients treated by definitive radiotherapy for variety of tumors. PATIENTS AND METHODS: Ten patients were selected for this study. They were treated by radical radiotherapy for variety of tumors, including non-Hodgkin's lymphoma, prostate, glottic larynx, anal canal, cervix, bladder, thyroid gland, and tonsil pillar. Five patients did not develop any significant late reactions (normally sensitive group, NS). The other five developed late complications in different normal tissues and organs that proved to be fatal in one patient (clinically hyper-sensitive group, HS). Fibroblast cultures were established from punch skin biopsy and radiosensitivity in vitro was measured. The survival fraction at 2 Gy (SF2) was calculated and compared between the two groups. RESULTS: SF2 ranged between 0.10 and 0.38 with a mean of 0.24. The mean SF2 for each of the NS and the HS groups were 0.31 and 0.17, respectively. The non-parametric rank test of Mann-Whitney shows that the difference between the two groups is statistically significant (p = 0.01). CONCLUSION: This study indicates that the in vitro radiosensitivity of skin fibroblasts is correlated with late complications in different organs and normal tissues following radiotherapy for variety of tumors. It also lends support to the existence of a common genetic component determining the radiosensitivity of cells targeted by the late effects of ionizing radiation.

Adult↗

PubMed1997

Determination of radiosensitivity in established and primary squamous cell carcinoma cultures using the micronucleus assay.

In this study, the cytokinesis-block micronucleus assay (CBMN) was used to measure radiosensitivity in three established cell lines (SCC-61, V175 and V134) and 10 primary cell cultures of squamous cell carcinoma (SCC) of the head and neck. Assessment involved optimisation of the assay to determine cytochalasin-B (CB) concentration and sampling time postirradiation. A much closer correlation between dose-response data measured in the clonogenic and micronucleus assays was found when the micronucleus assay was performed under standardised conditions for each cell line (2 micrograms/ml CB: 48 h postirradiation) instead of predetermined optimised assay conditions. This indicates that, for these SCC cell lines, the CBMN assay may be able to predict in vitro radiosensitivity. To be of clinical use in predicting radiosensitivity, the CBMN assay also needs to be evaluated with primary cell cultures. In this study, no relationship between micronucleus frequency at 2 or 6 Gy and patient clinical outcome 12 months following surgery and radiotherapy was seen. Similarly, no association between patient outcome and tumour stage, nodal stage and histology was observed. These CBMN assay data from the primary cell cultures are presently inconclusive as a measure of patient tumour radiosensitivity.

Carcinoma, Squamous Cell↗

PubMed2001

New antimetastatic hypoxic cell radiosensitizers: design, synthesis, and biological activities of 2-nitroimidazole-acetamide, TX-1877, and its analogues.

We designed, based on the molecular orbital (MO) calculation, synthesized, and evaluated the biological activities of the new antimetastatic hypoxic cell radiosensitizer, 2-nitroimidazole-acetamide, TX-1877, and its analogues. Each analogue has an electron-affinic imidazole group, an acetamide group and a certain hydrophilic group to control its biological effect, toxicity, and pharmacokinetics. In in vitro radiosensitization assay, most TX-1877 analogues, which have an electron affinity (EA) of more than 0.9 eV and partition coefficient (P) of more than 0.021, showed satisfactory enhancement ratios (ER > 1.60) at doses of I mM. On the other hand, imidazole analogues, such as TX-1908 (EA = 0.67 eV), TX-1910 (EA = -0.34 eV) and TX-1931 (EA = -0.37 eV), which have low electron affinities, had an ER of 1.31 or less. TX-1877 and KIN-806 effectively inhibited tumor regrowth when administered with irradiation in vivo at a dose of 0.4 mg/g. Tumor lung metastasis was inhibited by treatment with either TX-1877 or KIN-806 without irradiation at a dose of 0.4 mg/g. TX-1877 reduced markedly the mean number of metastatic lung nodules in comparison with KIN-806. Moreover, TX-1877 and KIN-806 enhanced macrophage and helper T lymphocyte infiltration for 3 weeks after drug treatment. TX-1877 shows a high EA value and has the C2 of HOMO localizing on N-methylamide and the C2 of LUMO localizing on 2-nitroimidazole group. The MO data might be useful for designing a bifunctional hypoxic cell radiosensitizer. TX-1877 and its analogues are potential antimetastatic hypoxic cell radiosensitizers, which would improve the efficiency of radiotherapy and quality of life in cancer treatment.

Animals↗

PubMedDate not supplied

[In vitro radiosensitivity of skin fibroblasts can identify a group of patients with complications in various health tissues after radiotherapy].

PURPOSE: A retrospective study of the in vitro radiosensitivity of skin fibroblasts derived from two groups of patients treated by definitive radiotherapy for a variety of tumors who either displayed or did not display severe complications. PATIENTS AND METHODS: Seven radiotherapy patients were selected: three were treated for head and neck, prostate and non-Hodgkin lymphoma tumors, and did not develop any significant complications (control group); four patients were treated for bladder, thyroid, head and neck and anal canal tumors and developed serious acute and especially late reactions (hypersensitive group). Primary cell cultures of skin fibroblasts were established and their radiosensitivity studied by the clonogenic assay after exposing to single radiation doses ranging between 1 and 8 Gy. RESULTS: The survival fraction at 2 Gy (SF2) ranged from 0.27 to 0.38, with a mean of 0.33 for the control group, and from 0.10 to 0.20 with a mean of 0.17 for the hypersensitive group. The Mann-Whitney non-parametric test showed that the difference between the two means was statistically significant (p = 0.03). CONCLUSION: The data are in favor of a correlation between the radiosensitivity of patients' fibroblasts and the reactions of different normal tissues to radiotherapy. This association supports the use of the clonogenic survival, or a surrogate test, as a predictive assay. The multiplicity of normal tissues and organs implicated in this association suggests the existence of genetic factors that determine, at least in part, the radiosensitivity of target cells involved in the expression of normal tissues complications following radiotherapy.

Aged↗

PubMed1992

2-Nitroimidazole dual-function bioreductive drugs: studies on the effects of regioisomerism and side-chain structural modifications on differential cytotoxicity and radiosensitization by aziridinyl and oxiranyl derivatives.

A series of 2-nitroimidazoles bearing side chains terminating in or containing aziridinyl and oxiranyl groups has been prepared, and the compounds were evaluated in vitro as hypoxia-selective bioreductively-activated cytotoxins and selected compounds tested for their radiosensitizing properties toward hypoxic mammalian cells. Compounds were either the regioisomers of analogues of the potent dual-functional 2-nitroimidiazole alpha-[(1-aziridinyl)-methyl]-2-nitro-1H-imidazole-1- ethanol (RSU-1069, 1) with additional methyl groups or related oxiranes of varying side-chain length and type. Oxiranyl derivatives showed little differential toxicity, and those tested were less effective as radiosensitizers, and although these properties were influenced by side-chain length, differences were not great. Aziridinyl compounds related to 1 but with increased side-chain lengths were unstable. Methylation of 1 in various regions had little effect on radiosensitization and no clear advantages over 1 as differential cytotoxic drugs. Progressive methylation at C-3 was found to increase toxicity but decrease hypoxia selectivity. Incorporation of a cyclohexane side chain in 1,2-cis-2,3-trans-3-aziridin-1-yl-2-hydroxy-1-(2-nitroimidazol+ ++-1- yl)cyclohexane (26) abolished hypoxia-selective toxicity and unexpectedly reduced radiosensitizing efficiency. Of the aziridines, 1-(2-nitro-1-imidazolyl)-2-methyl-3-(1-aziridinyl)-2-propanol (20) was comparable in efficacy to 1 as a bioreductively-activated cytotoxin with slightly lower aerobic toxicity; however, the prodrugs of 1 remain as preferred candidates for clinical evaluation.

Antibiotics, Antineoplastic↗

PubMed1990

Synthesis and evaluation of novel electrophilic nitrofuran carboxamides and carboxylates as radiosensitizers and bioreductively activated cytotoxins.

A series of 5-nitrofuran-2- and 3-carboxamides bearing alkylating side-chains has been synthesized and tested for their ability to radiosensitize selectively hypoxic Chinese hamster cells (V79) to the lethal effects of ionizing radiation and also for their ability to act directly and selectively as cytotoxic drugs on hypoxic V79 cells. The compounds were extremely efficient radiosensitizers of such cells in vitro and were more efficient than known nitroimidazoles of similar type. Their efficiencies as radiosensitizers correlated with their high electron affinity (E7(1] as measured by pulse-radiolysis. However the compounds showed little radiosensitizing activity towards KHT sarcomas in C3H mice. The compounds in this series of nitrofurans were generally more toxic towards hypoxic cells than towards oxic cells in vitro but were less effective upon the basis of a differential effect than were similar nitroimidazoles reported previously.

Amides↗

PubMed1979

Pharmacokinetic considerations in testing hypoxic cell radiosensitizers in mouse tumours.

Bilateral kidney ligation of mice immediately before injection of misonidazole (MIS) prolongs the plasma half-life of this radiosensitizer from about 2 h (in normal mice) to 10-11 h, similar to that in man. Kidney ligation does not, however, change the relative proportions of MIS and its O-demethylated metabolite, Ro-05-9963, for the first 12 h after MIS injection. Kidney ligation was used with the two radiosensitizers, MIS and Ro-05-9963, to investigate the influence of plasma half-life both on peak plasma levels and on the tumour/plasma ratio of sensitizer concentration in the EMT6 mouse tumour. Although the acute LD50 of Ro-05-9963 in normal mice was twice that of MIS, this apparent advantage was offset by peak tumour levels 50% or less of those achieved by equimolar injected doses of MIS. However, by comparing the plasma and tumour levels in mice in which the drug half-lives were prolonged by bilateral kidney ligation, it was concluded that the lower plasma and tumour levels of Ro-05-9963 were a result of its shorter plasma half-life, rather than of an intrinsic barrier to tumour penetration. Because of this rapid clearance, the radiosensitization produced by Ro-05-9963 was less than that produced by equimolar injected doses of MIS. As this difference did not occur in kidney-ligated mice, and hence would not be expected to occur in man, the comparison of MIS and Ro-05-9963 in mice produces an artificially low radiosensitization for Ro-05-9963 and possibly also for other compounds with short plasma half-lives. Although the short plasma half-life of Ro-05-9963 appeared to be responsible for its low peak plasma concentration, it did not produce a low tumour/plasma ratio. Within the limits of plasma nitroimidazole half-lives investigated (0.5-10 h) the tumour/plasma ratio was insensitive to plasma half-life, being 50-70% for both MIS and Ro-05-9963 in both normal and kidney-ligated mice. It is concluded that the common assumption that tumour/plasma ratios of MIS in the mouse are less than those in man is unjustified.

Animals↗

PubMed1981

Radiosensitivity of microscopic tumours of a transplantable mammary adenocarcinoma in mice.

Evidence is presented that microscopic tumours (of a transplantable murine mammary carcinoma, M8013X) grow faster than larger, palpable, tumours. Microscopic tumours are also more radiosensitive than larger tumours. The decrease in radiosensitivity in larger tumours is prevented to a large extent by misonidazole, which has no significant effect on the radiosensitivity of microscopic tumours. The retardation in growth rate which occurs after the fast microscopic growth is probably related to the appearance of hypoxic cells. Both the decrease in growth rate and the progressive development of hypoxia may be caused by the relatively poorer blood flow in larger tumours. Part of the radioresistance in "large" tumours ( approximately 250 mm3) seems to be due to factors other than hypoxia; maybe cell-kinetic factors also play a role. The intrinsic radiosensitivity of tumour cells in microscopic tumours was assessed by means of a modified latency test: the Dq and Do were 2.2 and 2.5 Gy respectively. A number of factors which may influence the reliability of these estimates are discussed.

Adenocarcinoma↗

PubMed1982

In vivo assessment of basic 2-nitroimidazole radiosensitizers.

The radiosensitizing efficiencies of 4 structural analogues of misonidazole (MISO) have been compared with that of the parent compound. Three of these were charged basic compounds, previously shown in vitro to be 10 times more efficient. Enhancement ratios were measured from pairs of tumour growth-delay curves for the mouse fibrosarcoma SA Fab. Two routes of administration and ranges of drug dose and intervals between injection and irradiation were tested. Drug concentrations in blood, brain and tumor were measured using high-performance liquid chromatography. The peak concentration in tumours coincided with the peak in radiosensitization: 20 min after i.v. injection and 40 min after i.p. injection. The concentration in tumours was similar for either route. Comparison of radiosensitizing efficiency on the basic of equal administered dose showed no difference between the 5 compounds, but after equimolar doses the charged compounds achieved lower tumour concentrations. Comparison of sensitizing efficiency on the basis of tumour concentration showed that they were 3 times more potent than MISO, as predicted from their higher electron-affinity. The resultant improvement in radiosensitization at low, clinically relevant, concentrations is so slight that any therapeutic benefit would depend on reduced drug toxicity in man.

Animals↗

PubMed1990

Enhancement of the radiosensitivity of two human tumour cell lines by hexamethylene bisacetamide.

The effect of the maturation-inducing polar solvent, hexamethylene bisacetamide (HMBA), on the radiosensitivity of two human tumour cell lines (clone A, a colon carcinoma; and EJ, a bladder carcinoma) was investigated. Exposure of clone A or EJ cells to HMBA resulted in a concentration-dependent increase in doubling time, a decreased plating efficiency and changes in cell morphology, which are consistent with the formation of a better-differentiated phenotype. Growth of clone A cells in 2 or 3 mM HMBA, followed by irradiation and plating into HMBA-free medium, resulted in a significant enhancement in radiosensitivity, as determined by colony-forming ability. A similar increase in radiosensitivity was detected for EJ cells; however, for these cells a concentration of 7 mM HMBA was required. The increased radiosensitivity caused by HMBA was observed primarily in the low-dose, shoulder region of the gamma-ray cell survival curves for both cell lines, which is reflected by an increase in the alpha component of the survival curve with essentially no effect on beta. These data indicate that HMBA can radiosensitise human tumour cells at concentrations and for exposure periods that can be achieved in the clinic.

Acetamides↗