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G P Raaphorst

Publications and source records attributed to G P Raaphorst.

At least 55 records · Page 3Linked to original sources
PubMed1996

Low-dose ionizing radiation decreases the frequency of neoplastic transformation to a level below the spontaneous rate in C3H 10T1/2 cells.

We have previously shown that chronic exposure of plateau-phase C3H 10 T1/2 cells to (60)Co gamma radiation at doses as low as 10 cGy protected the cells against neoplastic transformation by a subsequent large acute radiation exposure. We have also shown that this induced resistance to neoplastic transformation correlated with an increased ability to repair radiation-induced chromosome breaks. We now show that a single exposure of quiescent cells to doses as low as 0.1 cGy also reduces the risk of neoplastic transformation, from the spontaneous level to a rate three- to fourfold below that level. Higher doses, up to 10 cGy at the same dose rate (0.24 cGy/min), did not reduce the neoplastic transformation frequency further. This protective effect was seen only in irradiated cells that were allowed to incubate at 37 degrees C before release from contact inhibition. Cells released into low-density subcultures immediately after irradiation had unchanged neoplastic transformation frequencies. These results demonstrate that low or chronic exposure to radiation can induce processes which protect the cell against naturally occurring as well as radiation-induced alterations that lead to cell transformation. If similar processes are induced in human cells, the results also suggest that a single low dose, at background or occupational exposure levels, may in some circumstances reduce rather than increase cancer risk, a conclusion inconsistent with the linear no-threshold model of cancer risk from radiation.

Animals↗
PubMed1995

Correlation between Gd-enhanced MR imaging and histopathology in treated and untreated 9L rat brain tumors.

Gadolinium-based MR imaging contrast agents cause signal enhancement of intracerebral tumors on T1-weighted MR images because they cross the compromised blood-brain barrier, increasing the T1 relaxation rate of extracellular water. Tumor extent measured by Gd-enhanced MR imaging often does not agree with T2-weighted MRI or biopsy measurements, due to possible peritumoral barrier defects or infiltration of tumor cells beyond the region of enhancement. In this study, the 9L rat brain tumor model was used to measure the correlation between tumor size measured by Gd-enhanced and unenhanced MRI and histological measurements. There was excellent agreement between Gd-enhanced MRI measurements and histology. Morphological features of untreated 9L intracranial tumors and those treated with radiation and/or cisplatin were compared with histological features. No significant change in intracranial tumor size was detected in the treated animals up to 7 days following treatment, despite substantial tumor necrosis evident on histological analysis.

Animals↗
PubMed1995

Tissue preparation technique for microsphere assays of blood flow.

A simple method for preparing standardized tissue samples for microsphere assay of tissue blood flow is described. By reduction of tissue samples into a liquid state and centrifugation of the microspheres to the bottom of conical-shaped counting vials, the microspheres within all tissue and blood reference samples attain the same counting geometry. The validity and reproducibility of this technique has been established for planar-configured gamma-ray detectors in an in-situ porcine kidney model. A positive correlation coefficient of r = 0.99 was observed between the total kidney blood flow, as measured by a calibrated Transonic flow probe, and the microsphere reference sample technique.

Animals↗
PubMed1995

Stepdown hyperthermia in human melanoma cells: effects on protracted mild hyperthermia for survival and DNA polymerase inactivation.

Human melanoma cells have been used to evaluate whether stepdown heating (SDH) could increase the effectiveness of long-duration mild hyperthermia (LDMH). The effects of these treatments were also evaluated on cell survival and DNA polymerase inactivation. Short treatments (30 min) at 43 degrees C did not result in much SDH effect for subsequent protracted heating at 40 degrees C. The effect on DNA polymerases was also very small. However, heating at 44 degrees C for 30 min had a large SDH heating effect on subsequent heating at 40 degrees C and 41 degrees C. The SDH effect occurred mainly in the first 5-10 h of subsequent LDMH and, at longer heating times, the rate of cell killing was reduced. The 44 degrees C SDH effect was also observed on DNA polymerase inactivation. Comparing the degree of cell killing and polymerase inactivation showed a good correlation for the various SDH protocols.

Cell Death↗
PubMed1994

The kinetics of cellular recovery in exponential and plateau growth phase human glioma cells following gamma-irradiation.

PURPOSE: In this study the kinetics of recovery following irradiation was examined in a human glioma cell line. Specific objectives were: to determine whether recovery is mono- or biexponential in nature; to determine if recovery half-times are different in exponential and plateau growth phase cells; to compare recovery half-times as a function of dose or recovery levels; and finally, to compare the kinetics of sublethal damage recovery and potentially lethal damage recovery in plateau growth phase cells. METHODS AND MATERIALS: U-87MG cells were irradiated in exponential and plateau growth phases and then subjected to incubation at 37 degrees C for various periods of time following or between doses prior to assaying for survival. Survival recovery curves were fit to a sum of exponential terms. RESULTS: Potentially lethal damage recovery was monoexponential in both exponential and plateau growth phase cells and occurred at the same rate when isorecovery values were compared. Recovery half-times increased in an exponential manner within the observed dose range. Recovery between doses of radiation (sublethal damage recovery) proceeded at a slower rate than recovery following a single dose of radiation (potentially lethal damage recovery). CONCLUSIONS: This study suggests that potentially lethal damage recovery is a saturated process and that the recovery half-time may increase in a linear-quadratic exponential function of dose similar to the absolute recovery level. In addition, if iso-recovery levels are compared, the recovery half-time is similar in rapidly and slowly proliferating cell populations.

Cell Cycle↗
PubMed1994

Hyperthermia radiosensitization in human glioma cells comparison of recovery of polymerase activity, survival, and potentially lethal damage repair.

PURPOSE: DNA polymerase inactivation is compared to thermal radiosensitization and inhibition of damage recovery in human glioma cells. METHODS AND MATERIALS: Two human glioma cell lines (U87MG and U373MG) were exposed to hyperthermia and irradiation. Hyperthermia was given at 43 degrees C and 45 degrees C and DNA polymerase alpha + delta + epsilon and beta activities were measured. Hyperthermia was given at various times before irradiation and the degree of radiosensitization and polymerase activity was assessed at various times after heating. In addition the ability of cells to undergo repair of potentially lethal radiation damage was assessed for cells irradiated at various times after heating. RESULTS: Polymerase alpha + delta + epsilon and polymerase beta both recovered after heating but polymerase beta was faster and was complete in U373MG but not in the U87MG cell lines after 48 h incubation after heating (45 degrees C, 60 min). Incubation, between hyperthermia and irradiation resulted in a loss of radiosensitization and a loss of inhibition of repair of potentially lethal damage. These changes correlated well with recovery of polymerase beta but not with polymerase alpha + delta + epsilon. CONCLUSION: The correlation of polymerase beta activity and thermoradiosensitization and its recovery indicate that polymerase beta may be one of the mechanisms involved in thermoradiosensitization.

Cell Survival↗
PubMed1994

Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies.

PURPOSE: To review the human central nervous system pharmacology of cisplatin, factors that affect cisplatin uptake in tumors, and use alone and with radiation for the treatment of primary brain tumors. METHODS AND MATERIALS: The authors review their own prior published and unpublished experience and data published by other groups on the above issues. RESULTS: Cisplatin is one of the most active chemotherapy drugs available for the treatment of solid tumors. It is synergistic with several other agents, including radiation. While it attains only low concentrations in the normal central nervous system, concentrations and plasma-tissue transfer constants for human intracerebral tumors are comparable to those in extracerebral tumors. Tumor type appears to be a more important determinant of platinum concentration than is tumor location, and gliomas do achieve lower concentrations than do other intracerebral or extracerebral tumors. Several other factors have also been identified that correlate with concentrations of cisplatin achieved in human tumors. While cisplatin alone and in combination with other drugs does have some degree of efficacy against primary brain tumors, combining it with cranial irradiation has generally not resulted in any substantial improvement in outcome to date, although some individual studies have been somewhat encouraging. New approaches are currently under investigation. CONCLUSION: Human pharmacology studies provide a rationale for use of cisplatin in the treatment of human brain tumors, and human and in vitro studies suggest some manipulations that might potentially further augment tumor platinum concentrations. While clinical studies suggest that cisplatin combinations may be of some value vs. human primary brain tumors and brain metastases, and while in vitro studies suggest that cisplatin potentiates radiation efficacy, no combination of cisplatin plus radiation yet tested has appeared to be superior to radiation alone.

Brain Neoplasms↗
PubMed1994

Inhibition of potentially lethal damage recovery by altered pH, glucose utilization and proliferation in plateau growth phase human glioma cells.

Recovery from potentially lethal damage (PLD) has been measured in plateau growth phase human glioblastoma cells (U-87MG) under four postirradiation medium conditions. Recovery was maximal in depleted medium at an acidic pH, conditions which inhibit cellular proliferation. Compared with this control, PLD recovery (PLDR) was increasingly inhibited by alkalization of the existing medium (to pH 7.4), exchanging the old medium with fresh medium-pH acidified (to pH 6.8), and exchanging the old medium with fresh medium-pH unaltered (pH 7.4), respectively. These three medium adjustments were made at the time of irradiation. Increased glucose utilization (glycolysis) was detected postirradiation in all three cases, while increased proliferation was detected only when fresh medium was exchanged for old medium. Thus inhibition of PLDR has been correlated with increased glycolysis and increased proliferation during the recovery period. When acting together, these two processes provided almost complete inhibition. This study was revealed that the degree of inhibition may be related to the amount of glycolysis and/or proliferation occurring during the recovery period. Examining, in vitro, the range of PLDR achieved by postirradiation manipulation of medium pH may provide some indication of the range in PLDR that may be expected in vivo. Our study demonstrates that the effect of pH on glycolysis and proliferation may be important when determining the ability of a particular cell type to recover from PLD.

Cell Division↗
PubMed1994

Inhibition of potentially lethal and sublethal damage repair by camptothecin and etoposide in human melanoma cell lines.

We investigated the ability of camptothecin (CPT), an inhibitor of topoisomerase (topo) I, and etoposide (VP-16), an inhibitor of topo II, to potentiate X-radiation response and to inhibit the repair of potentially lethal damage (PLDR) and sublethal damage (SLDR) in confluent cultures of a radioresistant (Sk-Mel-3) and a radiosensitive (HT-144) human melanoma cell line. CPT or VP-16 were present both during irradiation and during the subsequent delayed plating period allowed for repair of X-radiation damage. When the direct toxicities of CPT or VP-16 were corrected for, we found that a dose of either drug that killed approximately 15% of the clonogenic cells potentiated the effects of radiation differentially on the cell lines. CPT and VP-16 inhibited the increase in survival brought about by delayed plating of HT-144 but not Sk-Mel-3 cells. In both cell lines, CPT inhibited SLDR but not PLDR. VP-16 also inhibited SLDR in both cell lines, however, in contrast with CPT, it also inhibited PLDR in HT-144 cells. Our results therefore suggest that either topo I and II are both implicated in the repair of X-radiation damage, or that the lesions formed by CPT and VP-16 with DNA are able to impair the processing of X-radiation repair. In addition, we found that in the absence of the topo inhibitors, the two cell lines repaired similar amounts of PLD from an isosurvival level. Sk-Mel-3, however, repaired significantly increased SLD from an isosurvival level (about three-fold, p < 0.05) compared with HT-144.

Camptothecin↗
PubMed1994

Sublethal radiation damage repair and its inhibition by hyperthermia in two human melanoma cell lines of different radiosensitivities.

Two human melanoma tumour cell lines, one radiation resistant and one radiation sensitive, were studied for their capacity for repair of sublethal radiation damage (SLDR) and for hyperthermia inhibition of radiation damage. The most resistant cell line demonstrated a survival curve with a large shoulder and a large SLDR capacity. The sensitive cell line was characterized by an exponential survival curve and had less SLDR capacity than the resistant line. Hyperthermia could inhibit SLDR in both cell lines and complete inhibition was achieved at 43 degrees C for 30 min. Hyperthermia was more effective after than before irradiation. The SLDR inhibition was greater in the resistant cell line, showing that hyperthermia may be an effective way to overcome resistance in melanoma, especially when such resistance stems from an increased SLDR capacity. In addition, relatively mild thermal treatments, easily achievable clinically, were sufficient to inhibit SLDR in melanoma cells.

Cell Line↗
PubMed1994

The survival of aerobic and anoxic human glioma and melanoma cells after irradiation at ultrahigh and clinical dose rates.

This in vitro study was undertaken to determine if ultrahigh dose rates could improve the radiation response of human tumors. Two cell lines, human glioma (U-87 MG), which is radioresistant, and human melanoma (HT-144), which is radiosensitive, were irradiated at ultrahigh and high dose rates under aerobic and anoxic conditions to determine if their oxygen enhancement ratios are modified by dose rate. In fact, the survival curves, and hence the oxygen enhancement ratios, were found to be independent of the dose rate. The oxygen enhancement ratio for glioma cells irradiated in plateau phase was 2.8 (+/- 0.3). The oxygen enhancement ratio was 2.7 (+/- 0.4) for melanoma cells in plateau phase and 2.8 (+/- 0.3) in exponential phase. These results indicate that there is no advantage in treating these tumors using ultrahigh dose rates instead of conventional dose rates.

Cell Hypoxia↗
PubMed1994

Comparison of thermoradiosensitization in two human melanoma cell lines and one fibroblast cell line by concurrent mild hyperthermia and low-dose-rate irradiation.

Two human melanoma cell lines, one radioresistant (SK-MEL-3) and one radiosensitive (HT-144), and a normal human fibroblast line (AG1522) were evaluated for thermoradiosensitization of low-dose-rate irradiation by concurrent mild hyperthermia (39-41 degrees C). None of the cell lines expressed chronic thermotolerance during heating at 39-41 degrees C. The SK-MEL-3 cells were the most heat sensitive, while AG1522 and HT-144 cells had the same sensitivity at 39 and 40 degrees C but HT-144 cells were more sensitive at 41 degrees C. All cell lines expressed thermal enhancement of radiosensitivity with heating during irradiation which increased with heating temperature. The SK-MEL-3 cells, which were the most resistant to radiation and demonstrated the greatest repair of sublethal damage (SLD) during low-dose-rate irradiation, had the greatest thermal enhancement of radiosensitivity, while the HT144 cells, which were the most sensitive and expressed little repair of SLD during low-dose-rate irradiation, had the smallest thermal enhancement of radiosensitivity. These data show that concurrent mild hyperthermia during low-dose-rate irradiation may be most efficacious in radiation-resistant tumor cells which express resistance through an enhanced capacity for repair of SLD.

Cell Line↗
PubMed1994

Radiation-induced adaptive response for protection against micronucleus formation and neoplastic transformation in C3H 10T1/2 mouse embryo cells.

We have monitored the end points of cellular survival, micronucleus formation and neoplastic transformation frequency to assess adaptation to ionizing radiation in the C3H 10T1/2 mouse embryo cell system. Plateau-phase cells were pre-exposed to an adapting dose of 0.1 to 1.5 Gy low-dose-rate gamma radiation 3.5 h prior to an acute challenge dose of 4 Gy. No adapting dose improved clonogenic survival detectably, whether the cells were plated immediately after the acute exposure or held in plateau phase for 3.5 h before plating. However, all chronic adapting doses resulted in both a reduction in micronucleus frequency in binucleate cells and about a twofold reduction in neoplastic transformation frequency per viable cell when cells were subsequently exposed to the 4-Gy challenge dose. Our data suggest that a low-dose-rate pre-exposure to ionizing radiation induces an adaptive response in C3H 10T1/2 cells, and that this response enhances DNA double-strand break repair when cells are subsequently exposed to a second radiation dose. This enhanced repair appears to be error-free since these adapted cells are also less susceptible to radiation-induced neoplastic transformation.

Adaptation, Physiological↗
PubMed1993

Postirradiation exposure to hypotonic saline shows normal damage processing in radiation-sensitive cell lines.

Three pairs of cell lines (one human and two Chinese hamster ovary (CHO) cell lines) each comprising a cell line with a normal radiation response and a radiation-sensitive mutant, were evaluated for recovery of potentially lethal damage (PLDR) and recovery of sublethal damage (SLDR). In all cases, the normal cell lines (GM1522, human; AA8-4 and K1, CHO) exhibited capacity for PLDR and SLDR was also normal in the two CHO lines. For the mutants (GM3395, human AT; V3 and 5-11, CHO) there was no ability for PLDR and SLDR was also absent in the two CHO cell lines. Postirradiation exposure to hypotonic NaCl solutions resulted in fixation of radiation damage in all the cell lines. This form of damage is repaired if left unperturbed after irradiation. This shows that cells have a large capacity for repair of this form of damage which accounts for much greater changes in survival than those observed in conventional PLDR experiments. These data show that the mutant cell lines retained their capacity to repair the damage which was susceptible to postirradiation fixation by anisotonic salt solutions. In addition, initial (i.e. preirradiation) DNA polymerase activities were measured in the four CHO cell lines; they were not correlated to radiation sensitivity.

Animals↗
PubMed1993

Changes in survival and potentially lethal damage recovery following periods of high and low metabolic activity in human glioma cells.

Radiation survival and recovery from potentially lethal damage has been measured in human glioblastoma cells as they progressed from an exponential to an extended plateau growth phase. Immediate plating (IP) survival following 7.5 Gy 60Co irradiation decreased from 2.3% for cells in exponential growth phase to 0.11% for cells held in an extended plateau growth phase with no change or adjustments made to the medium. Delayed plating (DP) survival decreased from 10% to 2.5%, respectively. Under these conditions, medium pH, rate of glycolysis, and proliferation status were monitored. IP survival was found to be sensitive to both proliferation status and the amount of time the cells spent in a metabolically quiescent state. Recovery ratios (DP surv./IP surv.) increased from 4.3 to 23, primarily due to IP survival decreasing at a greater rate than DP survival. Aerobic glycolysis was found to be responsible for approximately 42% of the glucose utilization. Metabolic activity (glycolysis) was increased by increasing the pH of the existing medium. Survival was measured 3 days after each pH adjustment to allow a new metabolic equilibrium to establish with a pH and rate of glycolysis comparable to that in control experiments that had no pH adjustments. Both IP and DP survival showed only slight decreases compared to control experiments, while the recovery ratio at the end of a 6-day plateau period remained the same as in control experiments. No additional cell growth or redistribution of cells within the cell cycle occurred. Thus a period of increased metabolic activity prior to irradiation is advantageous for both IP and DP survival as compared to a period of low metabolic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Cycle↗