Comparing the effectiveness of intranasal fentanyl spray with oral transmucosal fentanyl citrate in breakthrough pain.

Background: Breakthrough cancer pain (BTCP) is complex and severe, affecting quality of life and increasing hospitalisation. BTCP has a rapid onset that requires fast acting medication with minimal side effects.

Aim: This article compares the effectiveness of intranasal fentanyl spray (INFS) and oral transmucosal fentanyl citrate (OTFC) and their alleviation of BTCP within 10 minutes of administration.

Recruitment of TRRAP required for oncogenic transformation by E1A.

TRRAP links Myc with histone acetylases and appears to be an important mediator of its oncogenic function. Here we show that interaction with TRRAP is required for cellular transformation not only by Myc, but also by the adenovirus E1A protein. Substitution of the 262 N-terminal residues of Myc with a small domain of E1A (residues 12-54) restores Myc transforming function.

Differential formation and enhanced removal of specific cisplatin-DNA adducts in two cisplatin-selected resistant human testicular teratoma sublines.

Mechanisms of cisplatin resistance have been studied in two independently-selected sublines expressing clinically-relevant levels of resistance (3-fold) and established from a primary testicular teratoma obtained from previously untreated patients. Resistance was not associated with any significant modification in cellular uptake of cisplatin, in total glutathione levels or associated enzyme activities. However, immunochemical quantitation of specific platinum-DNA adduct formation and removal revealed that both resistant sublines were more proficient in repairing certain adducts than their generally repair deficient respective parental lines.

Multiple mechanisms of resistance in a series of human testicular teratoma cell lines selected for increasing resistance to etoposide.

Mechanisms of resistance to VP-16 were monitored in a series of sublines of the human testicular teratoma cell line (SuSa) derived following exposure either to fractionated X-irradiation (DXR-10) or to VP-16 using pulsed 24-hr exposures (VP10) or continuous exposure conditions (VPC2, VPC3 and VPC4). Orders of resistance expressed (ranging from 3- to 33-fold based on IC50 values derived from colony forming assays) were comparable with those likely to be encountered clinically. All of these resistant sublines showed some cross-resistance to VCR, and the 3 drug-selected sublines tested also proved cross-resistant to ADR.

Characterisation of the unusual expression of cross resistance to cisplatin in a series of etoposide-selected resistant sublines of the SuSa testicular teratoma cell line.

Three etoposide-selected resistant sublines of the SuSa testicular teratoma cell line expressing 9-, 21- and 33-fold levels of resistance, proved increasingly cross resistant to cisplatin with levels approximating to 3-, 4- and 6-fold in sublines VPC2, VPC3 and VPC4, respectively. Cisplatin resistance was not associated with any significant modifications in levels of total glutathione or associated enzyme activities. Decreased platinum (Pt) accumulation was detected, although this did not correlate either with total platination levels judged immunochemically or with peak induction of interstrand crosslinks (ISC) determined by alkaline elution.

Deficient repair of cisplatin-DNA adducts identified in human testicular teratoma cell lines established from tumours from untreated patients.

Germ cell tumour lines appear generally more sensitive in vitro to cisplatin than other cultured cell lines, reflecting their clinical responsiveness. We proposed (Cancer Res 1988, 48, 3019-3024) that cisplatin hypersensitivity, expressed by a testicular teratoma line (SuSa), might be explained by an inability to repair platinated DNA. We have now quantitated cisplatin cytotoxicity by clonogenic assay, and platinum (Pt)-DNA adduct formation and removal immunochemically in four other testicular teratoma continuous cell lines (GCT46, GCT27 clone 4, H32 and H12.

Differential cytotoxic effects of docetaxel in a range of mammalian tumor cell lines and certain drug resistant sublines in vitro.

The in vitro cytotoxic effects of docetaxel (Taxotere; RP56976, NSC688503) proved both time and concentration dependent. Amongst thirteen human cell lines from various tumor types, exposure to increasing concentrations of docetaxel over 24 hrs resulted in a plateau-shaped dose response curve, suggesting that increased cell kill becomes more dependent on increased exposure duration than on concentration. IC50 concentrations (reducing survival by 50%) ranged from 0.

Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines.

The expression of intrinsic resistance to cisplatin in two lung cancer cell lines, one derived from a small cell carcinoma (SW1271) and the other from an adenocarcinoma (A549), relative to a drug-sensitive small cell line SW900, was characterized by: (i) expression of cross-resistance to mitomycin C and cadmium chloride, but increased sensitivity to adriamycin and etoposide; (ii) significantly decreased cisplatin uptake; (iii) elevated levels of glutathione which could be reduced by buthionine L-sulfoximine resulting in significant sensitization of the cells to cisplatin; (iv) a lack of consistent modification of metallothionein content and expression of levels of glutathione S-transferase, glutathione reductase and glutathione peroxidase or of activities of DT-diaphorase or catalase; (v) significantly reduced total DNA-platination levels immediately following a 1 h cisplatin treatment with 10 micrograms/ml (33.3 microM); (vi) increased removal of Pt-GG and Pt-AG adducts by the A549 cells, consistent with increased repair capacity, but a lack of removal of these major adducts by the SW1271 cells indicative of tolerance of this drug-induced DNA damage. These data therefore provide evidence of differential formation, repair and tolerance of DNA damage following exposure of three human lung carcinoma cell lines to cisplatin.

Mechanisms associated with the expression of cisplatin resistance in a human ovarian tumor cell line following exposure to fractionated X-irradiation in vitro.

Interactions between cisplatin (CDDP) and irradiation are of potential significance for the combined modality treatment of cancer. Previous data have indicated that following in vitro exposure to X-irradiation certain tumour cells expressed resistance to CDDP. To identify parameters associated with this CDDP resistance, the human ovarian carcinoma cell line SK-OV-3/P was pre-exposed to fractionated X-irradiation (total dose: 50 Gy) in vitro.

Characterization of a cisplatin-resistant human ovarian carcinoma cell line expressing cross-resistance to 5-fluorouracil but collateral sensitivity to methotrexate.

In vitro exposure of the TR170 ovarian carcinoma cell line to six intermittent 24-h treatments with a 90% inhibitory concentration of cisplatin (CDDP) (0.15 micrograms/ml; 0.5 microM) resulted in a 2-fold stably resistant subline designated TR170/CP+ (B.

Anomalous relationship between cisplatin sensitivity and the formation and removal of platinum-DNA adducts in two human ovarian carcinoma cell lines in vitro.

Two human ovarian tumor cell lines (SK-OV-3 and TR175), established from patients previously treated with alkylating agents, but not with cisplatin, expressed greater than 23-fold differences in cisplatin sensitivities in vitro. Cisplatin resistance in SK-OV-3 cells appeared to be associated with increased levels of glutathione and activities of glutathione reductase and glutathione peroxidase, with reduced catalase activity. No significant modification of drug uptake was noted and there was only marginally lower (16%) total platination of DNA, measured immunochemically, in these cells compared with the more sensitive TR175 cell line.

A lack of detectable modification of topoisomerase II activity in a series of human tumor cell lines expressing only low levels of etoposide resistance.

Etoposide (VP-16) resistance is expressed following in vitro exposure of HN-1 and MCF-7 human tumor cells to the drug itself or to fractionated X irradiation. VP-16-selected sublines prove cross-resistant to Adriamycin, amsacrine and actinomycin D, whilst X-ray-pretreated sublines show cross-resistance to only actinomycin D. These differential responses, in the HN-1 series, are not associated with significant differences in amounts of immunoreactive topoisomerase (topo) II, altered topo-II catalytic activity of nuclear extracts or changes in susceptibility of the topo II to VP-16- or amsacrine-induced DNA-protein cross-link formation.

Lack of significant modulation of the formation and removal of platinum-DNA adducts by aphidicolin glycinate in two logarithmically-growing ovarian tumour cell lines in vitro.

Two recently established human ovarian carcinoma cell lines (JA-T and TR175) have been used to study the effects of aphidicolin glycinate (APG), a specific competitive inhibitor of DNA polymerase alpha (Ikegani et al. (1978) Nature, 275, 458-460), on the formation and removal of four platinum-DNA adducts. Logarithmically-growing cells were exposed to cis-diamminedichloroplatinum (II) (cisplatin) (10 micrograms, 33.

Differential expression of drug resistance following in vitro exposure of human tumour cell lines to fractionated X-irradiation.

We have established that drug resistance can be expressed following in vitro exposure of tumour cells not only to antitumor drugs but also to fractionated X-irradiation. These data therefore suggest a biological basis for the clinical problem of drug resistance that can occur in patients with previously irradiated tumors. These observations, if confirmed, have clinical implications for the combined modality approach and need to be considered when attempting to identify resistant tumour cells in clinical specimens with the aim of monitoring or identifying effective drug regimens.

An evaluation of the role of glutathione and its associated enzymes in the expression of differential sensitivities to antitumour agents shown by a range of human tumour cell lines.

Glutathione and its associated enzyme activities have been quantitated in a series of human tumour continuous cell lines expressing a range of in vitro sensitivities to certain antitumour agents. Fourteen different parental lines and 15 various drug- and X-ray-selected resistant sublines have been studied. Quantitative relationships between total glutathione levels and related enzyme activities and sensitivities to six clinically-useful antitumour drugs or X-rays, as judged by colony forming assays, have been determined by linear regression analysis.

Enhanced DNA repair and tolerance of DNA damage associated with resistance to cis-diammine-dichloroplatinum (II) after in vitro exposure of a human teratoma cell line to fractionated X-irradiation.

In vitro exposure of a human testicular teratoma continuous cell line to fractionated X-irradiation resulted in the expression of resistance to cisplatin. In two independently-derived sublines, designated SUSA-DXR13 and SUSA-DXR10 resulting from treatment with either 13 fractions of 1.5 Gy (dose required to reduce survival by 1 log) or 10 fractions of 3 Gy (dose required to reduce survival by 2 logs) respectively, the IC50 values for cisplatin were 2- and 3.

Comparative effectiveness of mitoxantrone and doxorubicin in overcoming experimentally induced drug resistance in murine and human tumour cell lines in vitro.

Using a range of cell lines of murine and human tumour origin in which relatively modest levels (2- to 17-fold) of drug resistance have been selected in vitro by exposure to a range of standard antitumour drugs, we compared the cytotoxic effects of doxorubicin (DOX) and mitoxantrone (MITO). In general, significantly lower concentrations of MITO than of DOX were required to achieve comparable cytotoxicity, confirming previously published data. MITO appears more generally effective against the murine L5178Y drug-resistant sublines than DOX, although there was no expression of collateral sensitivity to this newer agent.

Differential repair of platinum-DNA adducts in human bladder and testicular tumor continuous cell lines.

The formation and removal of four platinum-DNA adducts were immunochemically quantitated in cultured cells derived from a human bladder carcinoma cell line (RT112) and from two lines derived from germ cell tumors of the testis (833K and SUSA), following exposure in vitro to 16.7 microM (5 micrograms/ml) cisplatin. RT112 cells were least sensitive to the drug and were proficient in the repair of all four adducts, whereas SUSA cells, which were 5-fold more sensitive, were deficient in the repair of DNA-DNA intrastrand cross-links in the sequences pApG and pGpG.

Interactions between antitumor drugs and radiation in mammalian tumor cell lines: differential drug responses and mechanisms of resistance following fractionated X-irradiation or continuous drug exposure in vitro.

Drug-resistant mammalian tumor cell lines have been derived by either fractionated x-irradiation treatment or exposure to vincristine or etoposide (VP-16-213) in vitro. Analyses of the patterns of responses expressed by these differently derived, resistant cell lines have shown variations in responses to a range of antitumor drugs depending upon the agent used to induce resistance. However, all treated cell lines express resistance to vincristine and, with one exception, to VP-16-213.

Differential expression of collateral sensitivity or resistance to cisplatin in human bladder carcinoma cell lines pre-exposed in vitro to either X-irradiation or cisplatin.

Two sublines were derived from a human bladder carcinoma continuous cell line (RT112-P), one by exposure to fractionated X-irradiation (RT112-DXR8) and the other by continuous exposure to cisplatin (RT112-CP). RT112-DXR8 cells were 1.6- to 2-fold more sensitive to cisplatin and 2 analogues, carboplatin and iproplatin, compared with the parental line, whereas RT112-CP cells were 1.

Establishment and characterisation of three new human ovarian carcinoma cell lines and initial evaluation of their potential in experimental chemotherapy studies.

Three new human cell lines have been established from biopsy specimens of ovarian cystadenocarcinomas: line JA-1 was derived from a primary "solid" tumour from an untreated patient, whilst the other lines were derived from ascites from patients previously treated with chlorambucil plus either cyclophosphamide (TR175) or cisplatin (TR170). Their in vitro characteristics are compared with those of the established SK-OV-3 line of similar origin. Each line has a distinct morphology and expresses a unique isozyme profile and karyotype.