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G P Raaphorst

Publications and source records attributed to G P Raaphorst.

175 records · Page 10Linked to original sources
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Comparison of human tumour cell responses to cisplatin and ZD0473 with and without irradiation.

Three pairs of human tumour cell lines, with one line of each pair resistant to cisplatin, were used to compare the effects of cisplatin and ZD0473 on cellular toxicity and radiosensitization. Whilst all three cell line pairs had one line that was resistant to cisplatin, for ZD0473 the lung tumour HTB56cp and cervical carcinoma ME180 cell lines did not express resistance to their HTB56 and SHA counterparts, respectively. Only the ovarian carcinoma line A2780cp showed resistance to ZD0473 compared to its counterpart A2780S. For radiosensitization both cisplatin and ZD0473 show additive and subadditive effects in the ovarian carcinoma lines, and additive and superadditive effects in the cervical carcinoma and lung tumour cell lines. In fact in the lung tumour cell lines ZD0473 appeared to be a more effective radiosensitizer than cisplatin.

Adenocarcinoma↗
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A comparison of response to cisplatin, radiation and combined treatment for cells deficient in recombination repair pathways.

The responses of cells with mutated DNA repair pathways were compared for cisplatin, radiation and combination treatments. The knockout of the nonhomologous endjoining (NHEJ) pathway resulted in increased radiation sensitivity, but no change in cisplatin response in the mouse cells and increased radiosensitivity but decreased cisplatin sensitivity in chicken cells. The mutation of the homologous recombination repair (HR) pathway through XRCC3 in CHO cells resulted in increased radiation and cisplatin sensitivity and to a lesser extent for the Rad54 knockout in the DT40 chicken cells. The combination treatments of cisplatin and radiation showed that inhibition of the HR repair pathway resulted in super additive effects while the inhibition of the NHEJ pathway in DT40 had no effect. In mouse cells the knockout of the NHEJ pathway resulted in reduced super additivity compared to the parental cell lines. These data show that radiation, cisplatin and combination treatment damage is affected differently by the various DNA repair pathways, which could have a range of effects on combination treatments in tumour cells expressing different levels of DNA repair in the various repair pathways.

Animals↗
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The evaluation of thermal cisplatin sensitization in normal and XP human cells using mild hyperthermia at 40 and 41 degrees C.

The effect of protracted mild hyperthermia treatment at 40 and 41 degrees C given, concurrently with cisplatin, was evaluated in human normal AG1522 and human mutant XPA cells. While mild hyperthermia itself for up to 6 hours showed little to no toxic effects, it did result in significant sensitization of response to cisplatin treatment. Sensitization for the normal and mutant cell line was comparable, indicating that nucleotide excision repair (NER) probably does not have a role in this process. For the 41 degrees C heating, thermotolerance developed and heating times greater than 4 hours resulted in protective effects from cisplatin cytotoxicity. This was not observed for heating at 40 degrees C for up to 6 hours.

Antineoplastic Agents↗
PubMedDate not supplied

Evaluation of adaptive responses to cisplatin in normal and mutant cell lines with mutations in recombination repair pathways.

Cell lines mutant in specific DNA repair pathways were used to determine if these pathways are involved in adaptive responses. For these studies, the effect of deficiencies in homologous recombination repair (HR) were studied in the parental AA8 and mutant (irs)ISF cell line pair and for deficiencies in the nonhomologous endjoining (NHEJ) pathway in the mouse MEF parental and Ku80 mutant cell line pair. The results showed that the XRCC3 mutation in the HR-deficient mutant inhibited adaptive responses to low doses of cisplatin and radiation. The parental lines showed transient adaptive responses to both low-dose cisplatin and radiation treatment. For the mouse MEF and the Ku80 cells, no adaptive responses were observed in either cell line. However, there was an initial transient sensitization response followed by partial recovery. Thus, it appears that the HR repair system may be involved in the adaptive response to cisplatin and radiation. For the NHEJ repair system the question could not be answered since no adaptive responses were evident in the parental line.

Animals↗
PubMedDate not supplied

The in vitro effects of lonidamine combined with cisplatin in human small cell lung cancer cell lines.

Two human small cell lung cancer (SCLC) cell lines were used to evaluate the in vitro response to lonidamine and cisplatin exposure. The two cell lines both showed growth inhibition when exposed to lonidamine alone at concentrations greater than 50 micrograms/ml; however, one cell line (H69) was more sensitive. When cisplatin was combined with lonidamine a synergistic interaction was observed when cells were exposed to 10 microM cisplatin for 1 hour combined with lonidamine at concentrations of 50 micrograms/ml or greater. At a concentration of 25 micrograms/ml lonidamine combined exposure with cisplatin had no effect on cell growth or viability.

Antineoplastic Agents↗
PubMedDate not supplied

The effect of lonidamine alone and in combination with cisplatin on in vitro growth and viability of lung squamous cell carcinoma cell lines.

Two non small cell lung cancer (NSCLC) cell lines were tested in vitro to evaluate the effect of lonidamine, cisplatin and combinations of these two agents using different doses and schedules. Lonidamine alone at concentrations greater than 50 micrograms/ml caused inhibition of cell growth in both monolayer and spheroid cell cultures. Cisplatin at concentrations of 10-20 microM caused a concentration dependent toxicity and inhibited growth in monolayer and spheroid cell cultures. Combination treatment of lonidamine and cisplatin caused concentration dependent effects. For 25 micrograms/ml lonidamine, there was no additive and in some cases an antagonistic effect when used with cisplatin. For higher lonidamine concentrations (75 and 100 micrograms ml), an additive effect with cisplatin (10-15 microM) was observed. This effect saturated for cisplatin concentrations of 20 microM. These data show some potential for lonidamine and cisplatin combination therapy but treatment doses and schedules will have to be identified so that the additive effect can be achieved at concentrations clinically attainable.

Antineoplastic Agents↗
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Lonidamine can enhance the cytotoxic effect of cisplatin in human tumour cells and rodent cells.

Lonidamine combined with cisplatin treatment was tested in human glioma (U87MG) human squamous cell carcinoma (UMSCCl) and Chinese hamster (HA1) cells. The order of sensitivity to cisplatin was HA1 greater than U87MG greater than UMSCCl. Lonidamine caused little sensitization in U87MG cells, moderate sensitization in HA1 cells and large sensitization in UMSCCl cells. The degree of sensitization was correlated to the effect of lonidamine on cell growth. The degree of sensitization to cisplatin by lonidamine treatment was dependent on lonidamine exposure concentration, time and treatment sequence. Lonidamine shows potential for enhancement of cisplatin chemotherapy but this appears to be cell type specific and should be tested for cells derived from sites of clinical interest for such drug therapy.

Animals↗
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Evaluation of cisplatin response in three radiation resistant and three radiation sensitive cell lines.

The cisplatin response was studied in three radiation sensitive mutant cell lines each paired with normally responding or radiation resistant cell lines of parental or similar origin. The radiation sensitive cell lines V3 (CHO), AT5BI (human fibroblast) and HT144 (melanoma) also showed reduced or lack of ability to repair sublethal radiation damage. Also, V3 did not repair radiation induced DNA double strand breaks and AT5BI was excision repair deficient. None of these cell lines show any cross sensitivity to cisplatin treatment. Instead the response was more like the paired normally radiation responding cell lines, except for AT5BI which showed cisplatin resistance. Thus the mechanisms causing radiation sensitivity in the three cell lines are not involved in cisplatin sensitivity.

Animals↗
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Inhibition of potentially lethal damage recovery by cisplatin in a brain tumor cell line.

Radiation resistant tumours such as gliomas show enhanced capacity for potentially lethal damage recovery (PLDR), which can be inhibited by cisplatin. The 9L rat brain tumour cell line, like human glioma cell lines, shows a large capacity for PLDR. Cisplatin administered at 6 micrograms/ml for 1 hour immediately following acute irradiation (18 Gy) is shown to cause significant inhibition of PLDR, while 3 micrograms/ml causes little inhibition. Cisplatin-radiation treatment sequence affects PLDR inhibition, with maximum effect seen when cisplatin is administered immediately after irradiation, during the period of rapid cellular recovery. These data suggest that optimum interaction between radiation and cisplatin treatments can be achieved by maximizing intratumoural cisplatin levels during the post-irradiation recovery period.

Animals↗
PubMedDate not supplied

Cisplatin and mild hyperthermia in radiosensitization to low dose rate irradiation in human ovarian carcinoma cells.

Two human ovarian carcinoma cell lines, one parental and the other a cisplatin resistant derivative cell line, were evaluated for the efficacy of combined treatments of mild hyperthermia, cisplatin and low dose rate irradiation (LDRI). The data showed that cisplatin (1 or 3 micrograms/ml for 1 hour) combined with mild hyperthermia (40 degrees C for 1 hour) was effective for radiosensitization to LDRI in the parental cell line whether given before or after irradiation. In the cisplatin resistant variant, however, these treatments had little to no effect on LDRI response. Thus these data show that these treatments could be clinically effective if there is no cisplatin resistance. Our previous study showed that concomitant treatments could be effective in both parental and cisplatin resistant cell line (1).

Cell Survival↗
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Evaluation of apoptosis in four human tumour cell lines with differing sensitivities to cisplatin.

Four human tumour cell lines were evaluated for their ability to undergo apoptosis when subjected to cisplatin or hyperthermia treatment. In an ovarian carcinoma line (A2780s) and its derivative cisplatin resistant line (A2780cp) the variation in response was expressed for both the colony survival endpoint and the apoptosis endpoint. Apoptosis was measured by the number of floating cells, DNA agarose gels, and electron microscopy. In fact, cisplatin resistance was expressed to a higher level for apoptosis, than colony survival in the A2780cp cell line compared to the A2780s line. The melanoma cell line (Sk Mel-3) also showed induced apoptosis by cisplatin treatment while the glioma line (U87MG) showed little to no apoptosis in response to cisplatin treatment. Hyperthermia (43 degrees C for 1 hour) induced apoptosis in the human melanoma cell line but not in the glioma cell line. These data indicate that, while both cisplatin and hyperthermia can induce apoptosis in human tumour cell lines, the degree of induction is highly cell line dependent.

Antineoplastic Agents↗
PubMedDate not supplied

DNA topoisomerase I content of a pair of human melanoma cell lines with very different radiosensitivities correlates with their in vitro sensitivities to camptothecin.

In this study, we set out to determine if the differential sensitivities to CPT between a radioresistant (Sk-Mel-3) and a radiosensitive (HT-144) human melanoma cell line, and also between cultures with a different growth phase in each cell line, were related to endogenous differences in cellular transport of CPT or to DNA topo I catalytic activities and content. Cultures of HT-144 and Sk-Mel-3 cells in both the exponential, or plateau (i.e. confluent), phase of growth were compared. Cellular response to CPT was determined by clonogenic survival assay. Drug accumulation and efflux were determined using [3H]CPT. Topo I catalytic activity was determined from the ability of nuclear extracts prepared from the cells to relax supercoiled DNA plasmid. Nuclear extracts of the cells were also used to determine topo I content by western blotting. The significantly enhanced sensitivity of exponential-phase, relative to plateau-phase, cultures of both cell lines was related to an enhanced accumulation of [3H]CPT in one (i.e. HT-144), but not the other, cell line. Thus the higher sensitivity of exponential-phase cultures of HT-144 relative to those of Sk-Mel-3 can at least be partially accounted for on the basis of a relatively higher accumulation. However, a higher accumulation was not the reason why plateau-phase cultures of HT-144 were relatively more sensitive than those of Sk-Mel-3. Although there were no significant differences (at the p < 0.05 level) between the endogenous catalytic activities of topo I extracted from exponential- and plateau phase-cultures of both these cell lines, there was a trend for HT-144 cells to show higher endogenous topo I catalytic activities compared to Sk-Mel-3 cells. In contrast, topo I content was higher in exponential- relative to plateau phase-cultures of both cell lines, and in HT-144 relative to Sk-Mel-3 when cultures in a similar growth phase were compared. The relative differences in sensitivity to CPT observed in vitro between these two cell lines, and also between exponential- and plateau phase-cultures of each cell line, correlates best with topo I content rather than topo I catalytic activity or [3H]CPT transport.

Adult↗