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PubMed1991

Structure-activity relationships for tumour radiosensitization by analogues of nicotinamide and benzamide.

Nicotinamide has been shown in our laboratory and those of other investigators to be an effective radiosensitizer of a variety of mouse tumours, while producing little or no radiosensitization of normal tissues. Its mechanism of action is different from classical electron-affinic compounds and appears to be the result of improved tumour oxygenation. In this study we have synthesized 29 analogues of nicotinamide and benzamide and characterized them for their tumour radiosensitization and acute toxicity in mice. The data show that a wide range of additions to the nicotinamide and benzamide ring produce tumour radiosensitization similar to that produced by equimolar doses of misonidazole, but that substitutions of the amide tend to reduce radiosensitization. Other structure-activity relationships are evident. Although some compounds produce similar tumour radiosensitization to nicotinamide at equimolar doses, and are comparably low in acute toxicity, none appears sufficiently superior to supplant nicotinamide itself as a candidate for clinical trials. Thus these data provide evidence that nicotinamide, because of the extensive experience with its use in man, is likely to be the best drug in the benzamide-nicotinamide series for development as a radiosensitizer of human tumours.

Animals↗

PubMed1992

Chemical radiosensitizers in cancer therapy.

The development of effective low-LET radiation therapy for cancer has been hindered by the lack of consistent differential responses to radiation between tumor and normal tissues. One major difference between many solid tumors and the surrounding normal stroma is the presence of hypoxic foci in solid tumors due to the inadequate supply of nutritional needs as a result of the breakdown of microvasculature. Consequently, failure of conventional radiotherapy and local recurrences are in part attributed to the radioresistant hypoxic cell populations, present in the tumor. Local cure/control rates of a tumor can be increased only by an effective increase in the radiation dose. At the same time, an increase in such a dose would damage the oxic normal stroma, more than the hypoxic tumor cells. Hence, specific modification of tumor radiosensitivity by the use of chemical radiosensitizers, in combination with conventional radiotherapy, is an attractive alternative. Many clinicians and radiotherapists are skeptical about the outcome of using radiosensitizers in patients. Nevertheless, a vast amount of information is currently available regarding the first- and second-generation radiosensitizers both in murine and in human tumors. As a result, it is hoped that eventually a radiosensitizing drug would be discovered/synthesized that will overcome the drawbacks so far encountered in their use in the clinic. In this article, the development of chemical radiosensitizers since the early sixties, the basis for their selection, their mechanism(s) of action, and the results obtained with the various groups of radiosensitizers are reviewed.

Animals↗

PubMed1992

Intrinsic radiosensitivity of normal human fibroblasts and lymphocytes after high- and low-dose-rate irradiation.

The existence of heritable radiosensitivity syndromes and clinical observations in radiotherapy patients suggests that human cellular radiosensitivity differs among individuals. We report here an in vitro study of radiosensitivity in 30 fibroblast and 29 lymphocyte cultures obtained from cancer patients and controls. In 25 cases, both fibroblasts and lymphocytes were obtained from the same donors. Fibroblasts were cultured from skin biopsy samples, and peripheral T-cell lymphocytes were cultured from blood. Clonogenic survival assays were performed by using high- and low-dose-rate irradiation; lymphocytes were in G0 phase and fibroblasts in confluent plateau phase. Various end points were calculated and compared (i.e., surviving fraction at 2 Gy, initial slope of the survival curve, and doses resulting in 10 and 1% survival, respectively). Depending on the end point, the coefficient of variation of the survival parameters ranged from 31 to 68% for lymphocytes and 21 to 41% for fibroblasts following high-dose-rate irradiation. Similar ranges were obtained after low-dose-rate irradiation. Variance analysis performed on replicate assays in cultures derived from the same patient showed that variation due to technical or sampling errors was significantly lower than variation between individuals (P = 0.00034 and 0.014 for fibroblasts and lymphocytes, respectively). No correlation was observed between the radiosensitivity of lymphocyte and fibroblast cultures derived from the same donors. We conclude that there is significant variation in normal cell radiosensitivity among individuals. On the other hand, comparisons of lymphocyte and fibroblast radiosensitivities suggest that tissue-specific characteristics, such as differentiation status, may variably modulate radiosensitivity.

Breast Neoplasms↗

PubMed1992

4-Fluorobenzylamine and phenylalanine methyl ester conjugates of 2-nitroimidazole: evaluation as hypoxic cell radiosensitizers.

We have synthesized two 2-nitroimidazole derivatives and evaluated their hypoxic radiosensitization properties. The first, a 4-fluorobenzylamine conjugate of 2-nitroimidazole (PK-110), was designed so that it could also be labeled with the F-18 and used for positron emission tomographic imaging of hypoxia. The second, the L-phenylalanine methyl ester conjugate of 2-nitroimidazole (PK-130), was designed in an attempt to exploit amino acid transport channels to enhance drug transport into the tumor. The effects of these drugs (and SR-2508, for comparison) in vitro on the aerobic and hypoxic radiosensitivity of Chinese hamster V79 cells were evaluated using clonogenic assays. PK-130 and PK-110 at 0.1 and 1.0 mM were more efficient hypoxic cell radiosensitizers than obtained with 1.0 mM SR-2508. Marginal aerobic radiosensitization was observed for 1.0 mM treatment with PK-130 and PK-110, however, no aerobic radiosensitization was observed at 0.1 mM. Glutathione (GSH) depletion (less than 5% of control levels) by L-buthionine sulfoximine (BSO) further enhanced the SER for both PK-130 and PK-110 at 0.1 mM to 3.2 +/- 0.63 and 2.4 +/- 0.16, respectively. The results of this study encourage the in vivo tumor radiosensitization evaluation of PK-130 and PK-110.

Animals↗

PubMed1992

Steepness of the clinical dose-control curve and variation in the in vitro radiosensitivity of head and neck squamous cell carcinoma.

Inter-tumour heterogeneity in radiobiological parameters has been proposed as an explanation for the quite shallow dose-response curves for local tumour control after radiotherapy observed in clinical data. Variability in the intrinsic radiosensitivity is potentially a very strong source of variation in local control. A method is presented for forcing such variability into a direct analysis (maximum-likelihood estimation) of tumour control data. The method is used to reanalyse a series of local tumour control data in 181 patients with squamous cell carcinoma of the oropharynx taking the distribution of in vitro radiosensitivities from an independent series of patients into account. It is concluded that direct application of the in vitro radiosensitivities leads to an unrealistically high estimate for the number of target cells per cm3. A more realistic fit is obtained after including a dose-modifying factor to correct for the apparent difference between in vitro and clinical radiosensitivities. The value of this factor is estimated at 2.4 with approximate 95% confidence interval (CI) (1.3, 5.9). It is suggested that hypoxia plays a role in reducing the radiosensitivity of tumours in clinical radiotherapy. Using this method provides more biologically reasonable estimates of other radiobiological parameters. The target-cell doubling time during treatment is estimated at 3.2 days with 95% CI (1.7, 8.7) days. Estimates of the target cell density in typical patients vary between 1.8 x 10(-6) and 6.6 x 10(-4) when the delay before accelerated tumour growth is assumed to vary between 0 and 28 days. Using the method presented here, the shallow clinical dose-control curve is interpreted as a superposition of quite steep dose-response relationships in individual patients. The steepness of the dose-control curve for a typical patient is characterized by a normalized dose-response gradient (the percentage change in tumour control for a 1% change in total dose) of 7.3 after stratification for intrinsic radiosensitivity as compared with 1.6 if such stratification is not performed.

Carcinoma, Squamous Cell↗

PubMed1992

Differential expression of proteins in radioresistant and radiosensitive human squamous carcinoma cells.

BACKGROUND: Previous studies support a genetic basis for cellular radioresistance. The associated biochemical and molecular events, however, are not fully understood. PURPOSE: We investigated the differential protein pattern as a molecular determinant of resistance or sensitivity of head and neck squamous carcinoma cells to ionizing radiation. METHODS: Using two-dimensional polyacrylamide gel electrophoresis followed by computer-assisted quantitative analysis, we compared the protein profiles of three relatively radioresistant and three relatively radiosensitive head and neck squamous carcinoma cell lines (previously characterized by in vitro and clinical parameters as radioresistant or radiosensitive) to determine which proteins were consistently expressed or enhanced in the radioresistant compared with the radiosensitive phenotype. RESULTS: Our analysis indicated that 14 proteins were preferentially expressed in the radio-resistant cell lines SQ-20B, JSQ-3, and SCC-35, with one protein (molecular mass of 92 kd and pI of 5.5) distinctly expressed in the radioresistant cell lines. Four proteins were enhanced by greater than 10-fold, three were enhanced fivefold to 10-fold, and six were enhanced twofold to fivefold in the radioresistant cell lines. In addition, we observed a second set of 15 proteins preferentially expressed in the radio-sensitive cell lines SQ-9G, SQ-38, and SCC-9. A 40-kd protein (pI 7.1) was distinctly expressed in the radiosensitive cell lines. The remaining radiosensitive cell-specific proteins were enhanced by greater than 10-fold (two proteins), fivefold to 10-fold (two proteins), or twofold to fivefold (10 proteins) compared with their counterparts in the radioresistant cell lysates. CONCLUSION: These results provide evidence for differential protein expression associated with phenotypic expression of cellular radioresistance or radiosensitivity. IMPLICATIONS: This study will facilitate the characterization of these proteins correlated with the radiation response-specific phenotype.

Carcinoma, Squamous Cell↗

PubMed2026

CRISPR Screen Identifies HDAC3 as a Novel Radiosensitizing Target in Small Cell Lung Cancer.

Small cell lung cancer (SCLC) is an aggressive malignancy, with most patients presenting with prognostically poor extensive-stage disease. Limited progress in standard care stresses the urgent need for novel therapies. Radiotherapy offers some survival benefit for selected patients with SCLC but could be enhanced with radiosensitizers. In this study, we identify HDAC3 as a novel radiosensitizing target in SCLC using a CRISPR knockout screen and demonstrate its efficacy and mechanism. SBC5 cells were transduced with a custom EpiDrug single-guide RNA library and treated with ionizing radiation (IR) to identify radiosensitizing genes. HDAC3 emerged as a candidate and was validated through genetic knockdown and pharmacologic inhibition (RGFP966) in multiple SCLC cell lines. Both approaches enhanced radiosensitivity, as shown by cell viability (dose modification factor10 = 1.14-1.69) and clonogenic assays (dose modification factor10 = 1.16-1.41). We assessed changes in chromatin accessibility by assay for transposase-accessible chromatin using sequencing and IR-induced DNA damage and repair using γH2AX foci detection, double-strand break (DSB) repair assays, and immunoblotting of repair proteins. HDAC3-deficient cells exhibited increased chromatin accessibility, greater IR-induced DSBs, and impaired repair capacity, resulting in persistent DNA damage. This repair defect sensitized cells to PARP inhibitors, for which combining RGFP966 with olaparib or talazoparib produced additive to synergistic effects. In SCLC xenograft models, HDAC3 knockdown or RGFP966, combined with IR, achieved significant tumor growth inhibition. Collectively, we identified HDAC3 as a novel radiosensitizing target in SCLC. Its functional loss increased the generation and persistence of IR-induced DNA DSBs, effectively sensitizing SCLC cell lines and xenografts to IR, providing a potential radiosensitization strategy to treat SCLC.

Humans↗

PubMed1992

Increased radiosensitivity of cell lines derived from a Down's syndrome patient with ocular telangiectasia.

Studies on radiosensitivity of cells from Down's syndrome (DS) patients were stimulated by the observation of their increased susceptibility to leukemia. While lymphocytes from DS patients were found to consistently show increased chromosomal aberrations after exposure to ionizing radiation, conflicting reports have been published on the radiosensitivity of fibroblasts and lymphoblastoid cell lines (LCL) derived from these patients. In the present study, cultured skin fibroblast lines developed from a DS patient with ocular telangiectasia and five normal subjects were compared for both cell killing and chromosomal aberrations (breaks, translocations, inversions, dicentrics, and rings) after low dose-rate gamma-irradiation. The LCLs developed from the patient and two normal persons were also compared for chromosomal radiosensitivity using the same irradiation protocol. A comparison of the D10 (radiation dose resulting in 10% survival) values estimated from the survival curves and the frequencies of induced chromosome aberrations in different cell lines showed that the DS cells were more radiosensitive than the respective controls. The increased cellular radiosensitivity of the DS patient reported here could be due to a combination of genetic factors (DS plus a gene for hypersensitivity to radiation) and, thus, may not be representative of all DS patients. Alternatively, the use of low dose-rate irradiation could be a factor in revealing the radiosensitivity of DS fibroblasts in general.

Cell Division↗

PubMed1976

Cytological factors and their predictive role in comparative radiosensitivity: a general summary.

Various cytological factors, including interphase chromosome volume (ICV), nuclear volume (NV), cell volume, DNA content per nucleus and per chromosome, have been reviewed to determine their usefulness as indices to predict radiosensitivity. Fourteen topics are discussed. They are: a historical development of the concept of using karyotypic features to estimate radiosensitivity; interrelationships between cellular parameters; relationship of the karyotype to the duration of mitosis and meiosis; relationships between chronic and acute irradiation and ICV using several radiobiological end points for woody and herbaceous species; correlations between dose and cellular parameters ftween chromosome aberrations and cellular characteristics after chronic irradiation; polyploidy and plant radiosensitivity; radiation-induced petal mutations in plants and their relationship to cellular parameters; correlations between mean survival time facter irradiation and cellular parameters in amphibians and higher plants; correlations between radiobiological end points and cellular parameters after whole-body irradiation in amphibians. insects and mammals; correlations between radiosensitivity and cellular parameters in diverse single-cell organisms; correlations between radiobiological end points and cellular parameters in higher plants irradiated with neutrons and the value of cell parameters to estimate relative biological effectiveness (RBE); and energy absorption and trends in radiosensitivity among species and radiobiological end points. It is concluded that ICV is usually the most useful parameter for predicting radiosensitivity.

Amphibians↗

PubMed1978

Hypoxic cell radiosensitization by 8-methoxypsoralen.

8-Methoxypsoralen has been shown to act as a radiosensitizer of hypoxic bacteriophage and bacteria. Radiosensitization of bacteriophage requires irradiation in the presence of excess scavenger. Bacterial radiosensitization requires deficiencies in uvr and rec genes. For the drug to be effective it must be present during irradiation. Pulse radiolysis studies have shown that, like electron-affinic radiosensitizers, 8MOP can efficiently oxidize free radicals. Unlike oxygen and most electron-affinic radiosensitizers 8MOP does not act in a purely dose-modifying fashion, and can radiosensitize beyond the oxygen effect.

Coliphages↗

PubMed2026

Linking MRI radiomics to transcriptomics-based radiosensitivity in lower-grade glioma: A radiogenomic framework.

BACKGROUND: RSI is a transcriptomics-based biomarker associated with radiotherapy outcomes, but its clinical application is constrained by the requirement for tumor tissue and RNA sequencing. This study investigates whether MRI-derived radiomic features can reflect RSI-defined intrinsic radiosensitivity in lower-grade glioma.This addresses a critical gap arising from the limited availability of matched imaging and genomic data in routine clinical practice. METHODS: MRI-derived radiomic features were extracted from FLAIR images of lower-grade glioma patients obtained from TCIA and matched with transcriptomic data from TCGA. A total of 107 patients with both MRI and RNA sequencing data were included in the radiogenomic analysis. Radiomic features were ranked using a Borda-based ensemble feature selection strategy. Five supervised machine-learning classifiers were trained to predict RSI-based radiosensitivity classification, and model interpretability was assessed using SHAP within radiogenomic framework. RESULTS: Classification performance increased with feature number and stabilized at compact subset of 13 radiomic features. Logistic regression showed stable performance with an AUC of 0.82 (95 % CI: 0.71-0.93). SHAP analysis indicated that heterogeneity-related texture features were dominant contributors to model predictions, with many associated with the RR phenotype, while others were linked to the RS phenotype. CONCLUSION: An MRI-based radiomic signature enables non-invasive prediction of RSI-defined radiosensitivity in lower-grade glioma. Rather than offering an immediately deployable clinical tool, this study establishes a proof-of-concept radiogenomic framework demonstrating that intrinsic radiosensitivity, traditionally assessed through invasive molecular assays, can be approximated using quantitative imaging features. These findings highlight the potential of imaging-based radiosensitivity assessment and provide a foundation for future radiogenomic investigations.

Lower-grade glioma↗

PubMed2026

DDX21 Enhances Radiosensitivity in Head and Neck Squamous Cell Carcinoma by Suppressing MK2-Mediated DNA Damage Response.

Radioresistance remains a significant challenge in the radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC). However, the biological factors that govern sensitivity to this therapy are not well-understood. The DEAD-box family is known for its role in genome stability, and inextricably linked to the radiotherapy resistance of tumors. This study found the role of the RNA helicase DDX21 in regulating radiosensitivity through extensive data mining. High DDX21 expression predicted improved survival after postoperative radiotherapy. Overexpression of DDX21 increased radiosensitivity in vitro and in vivo, whereas depletion promoted radioresistance. In vitro, DDX21 enhanced radiation-induced DNA damage, genomic instability, and apoptosis by binding MK2 and suppressing MK2 phosphorylation independently of p38 activity. Meanwhile MK2 inhibition restored and further augmented radiosensitivity in DDX21-deficient cells and xenografts by increasing DNA damage and apoptosis. Overall, DDX21 regulates radiosensitivity in HNSCC by suppressing MK2 signaling and modulating the radiation-induced DNA damage response. Its expression may serve as a potential biomarker associated with radiosensitivity, and MK2 inhibition offers a promising approach to overcome radioresistance in tumors with low DDX21 expression.

DDX21↗

PubMed1991

Radiosensitivity of small-cell lung cancer xenografts compared with activity of c-myc, N-myc, L-myc, c-raf-1 and K-ras proto-oncogenes.

Oncogenes of the myc family c-raf-1 and K-ras have been reported to modulate radiosensitivity. We examined the possible relationship between in vivo radiosensitivity to single-dose irradiation with 3-10 Gy, and activity of these proto-oncogenes in 2 sets of small-cell lung cancer (SCLC) xenografts, the CPH and the GLC series. CPH-54A and CPH-54B are in vitro-derived subclones of a SCLC cell line, while the GLC tumours were established as cell lines from a patient during longitudinal follow-up. Both tumours were later transferred into nude mice. CPH-54A was more sensitive to single-dose irradiation than CPH-54B, while, with respect to the 3 GLC tumours examined, GLC-16 was most sensitive, followed by GLC-14 and GLC-19. The CPH tumours expressed similar amounts of c-myc and c-raf-1 mRNA, and neither expressed N-myc or L-myc. GLC-14 expressed N-myc and c-raf-1 mRNA but no c-myc. GLC-16 and GLC-19 expressed identical amounts of c-raf-1 and high levels of c-myc mRNA, but neither expressed N-myc or L-myc. None of the tumours was mutated at codon 12 or K-ras. Our results show that SCLC xenografts with different radiosensitivity may express identical amounts of some of the proto-oncogenes reported to modulate radiosensitivity. Thus, factors other than activation of the examined proto-oncogenes must be involved in causing the differences in radiosensitivity found in the SCLC xenografts. Possible long-term effects of irradiation on proto-oncogene expression was examined in xenografts of GLC-16, following regrowth after single-dose irradiation. No long-term difference in expression of c-raf-1 or c-myc mRNA was detected between control tumours and tumours irradiated with 5 or 10 Gy.

Animals↗

PubMed1978

Radiosensitivity of different B and T subpopulations of lymphocytes in the mouse spleen.

X-irradiation was used as a tool to investigate the radiosensitivity of different B and T precursor subpopulations as detected by three in vitro culture systems. The culture systems utilized in this study included antigen reactive cell assays (ARCA), polyclonal mitogen assays (PMA), and polyclonal effector cell assays (PECA). The order of radiosensitivity of these systems in both the B and T cell series was ARCA greater than PMA greater than PECA (D37 values for B cell responses: ARCA = 88.8 R, PMA = 125 R, PECA = 223 R; D37 values for T cell responses: ARCA = 160 R, PMA = 441 R and PECA = 1095 R). With all assay systems the B cell response was more radiosensitive than the T cell response. The extrapolation number (n) from the radiation survival curves was approximately 2.0 for T cell responses and approximately 1.0 for B cell responses. The value of 1.0 for B cell responses suggest that their extreme radiosensitivity may be due in part to a lack of repair mechanisms. These findings also suggest that the more primitive precursor cells are more apt to undergo cellular proliferation upon activation and that this event is more radiosensitive than is the final differentiation event of precursor cells into a progeny of functional end-stage cells.

Animals↗

PubMed1992

Radiosensitivity measurement of keratinocytes and fibroblasts from radiotherapy patients.

Genetic diversity is believed to influence cellular radiosensitivity and individual variability in normal tissue reactions to radiotherapy. To measure normal cell radiosensitivity in vitro, we investigated a culture technique that yields keratinocyte and fibroblast cell cultures from small skin biopsy samples (average weight 32 mg). This technique uses 3T3 NIH cells as feeder cells, culture medium containing dialyzed fetal calf serum, low calcium, and various growth factors for keratinocyte growth. A calcium concentration of 4 x 10(-3) M and the use of lethally irradiated NIH 3T3 feeder cells were critical to the success of this method. Primary keratinocyte cultures were successfully obtained from nine biopsy specimens, and radiosensitivity measurements were obtained in six of the resulting strains. Keratinocytes were, in general, more radioresistant than fibroblasts derived from the same specimen. We conclude that radiosensitivity assessment of keratinocyte and fibroblast cultures derived from small punch biopsy specimens is feasible. Further studies can now be carried out to determine the degree of variability between individuals and the relationship between in vitro keratinocyte and fibroblast radiosensitivity and their value in predicting normal tissue responses to radiotherapy.

Cell Survival↗

PubMed1991

Aerobic radiosensitization by SR 4233 in rodent and human cells: mechanistic and therapeutic implications.

Mammalian cells surviving exposure to the bioreductive, cytotoxic agent SR 4233 under hypoxic conditions are sensitized to X-irradiation under aerobic conditions (and in the absence of drug). Fits of both the single-hit, multi-target and linear-quadratic expressions to survival data, as well as direct measurement of surviving fractions after a dose of 2 Gy, indicate that the aerobic radiosensitization produced by SR 4233 can increase both the initial and final 'slopes' of the X-ray survival curve. The amount of radiosensitization produced, and whether the modification is principally in the slope or shoulder region of the survival curve, varies from cell line to cell line. Rodent cells are radiosensitized equally whether the drug treatment is given immediately before or after, the irradiation, but human cells are only sensitized for SR 4233 exposure administered before irradiation. Using rodent CHO cells, time-course experiments for SR 4233 and X-rays given in sequence, in which an interval of up to 2 h was interposed between the treatments, reveal different kinetics for the loss of radiosensitization depending on whether the hypoxic drug exposure was given before or after the aerobic irradiation. When SR 4233 treatment is given pre-irradiation, the radiosensitization effect persists for at least 2 h, but it does not when drug is given after irradiation. Taken together, the finding of a difference between rodent and human cells with respect to post-irradiation sensitization by SR 4233, and the differing time-course kinetics for this effect as a function of how the drug and radiation are sequenced, suggest that while SR 4233 behaves in a radiomimetic manner in most respects, there may be subtle differences in the nature of the lesions produced by the drug, the important cellular targets for this damage, and/or the cell's management of the damage.

Aerobiosis↗

PubMed1991

Enhancement of SR 2508 (etanidazole) radiosensitization by buthionine sulphoximine at low-dose-rate irradiation.

SR 2508 (etanidazole) (1 mM) or buthionine sulphoximine (BSO, 50 microM) or both drugs together did not radiosensitize oxic V79 Chinese hamster cells irradiated at either an acute dose rate (2.35 Gy/min) or at a low dose rate (0.117 Gy/min). BSO pretreatment (15 h at 37 degrees C) depleted cellular glutathione (GSH) to less than or equal to 1% of control level and radiosensitized hypoxic cells at both dose rates with an enhancement ratio (ER) of 1.2. SR 2508 alone radiosensitized hypoxic cells equally at both dose rates with an ER of 1.5. However, ER values of 2.2 and 2.5 were obtained with 1 mM SR 2508 in GSH-depleted cells at acute and low dose rate, respectively, with no significant difference between the two, i.e. there is no dose rate dependence for this potentiation. Since BSO increases SR 2508 radiosensitization and the combined BSO + SR 2508 treatment is extremely cytotoxic to hypoxic cells, our results suggest that combining BSO with SR 2508 will be useful in brachytherapy as well as external-beam therapy if the toxicity from both drugs in vivo is less than the gain in radiosensitization achieved.

Animals↗

PubMed1977

Corynebacterium parvum-induced radiosensitivity and cycling changes of hematopoietic spleen colony-forming units.

Ten days after total-body irradiation with 550 rads of b0Co, spleen colonies were observed in adult C57BL mice. A change in radiosensitivity induced by Corynebacterium parvum, as measured by increased numbers of colony-forming units that survived the 550 rads, began shortly after C. parvum stimulation and extended for at least 7 days before irradiation. C. parvum given 4-24 hours before, followed by high specific activity [3H]thymidine (HSATT) 1 hour before total-body irradiation greatly reduced survival of the stem cells that formed spleen colonies (CFUs) and CFUs radiosensitivity to control levels. The HSATT sensitivity by "suicide" assay in vivo and the time-response change in radiosensitivity corresponded with the decrease in radiosensitivity, which showed that CFUs were stimulated by C. parvum administration and entered the S-phase shortly after stimulation. The data indicated a resting population close to the S-phase. After stimulation, this population entered S-phase. Syngeneic mouse lymphoma cells injected iv 24 hours earlier did not elicit any effect as a stimulus to CFUs radiosensitivity change.

Animals↗