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K D Bagshawe

Publications and source records attributed to K D Bagshawe.

At least 19 recordsLinked to original sources
PubMed1992

Computer system for assisting with clinical interpretation of tumour marker data.

OBJECTIVE: To design and evaluate a computer advisory system for the treatment of gestational trophoblastic tumour. DESIGN: A comparison of clinicians' treatment decisions with those of the computer system. Two datasets were used: one to calibrate the system and one to independently evaluate it. SETTING: Department of medical oncology. PATIENTS: Computerised records of 290 patients with low risk gestational trophoblastic tumour for whom the advisory system could predict the adequacy of treatment. The calibration set comprised patients admitted during 1979-86(227) and the test set patients during 1986-89(63). MAIN OUTCOME MEASURES: The system's accuracy in predicting need to change treatment compared with clinicians' actions. The mean time faster that the system was in predicting the need to change treatment. RESULTS: On the calibration dataset the system was 94% (164/174) accurate in predicting patients whose treatment was adequate, recommending change when none occurred in only 10 (6%) patients. In patients whose treatment was changed the system recommended change earlier than clinicians in 39/53 cases (74%), with a mean time advantage of 14.9 (SE 2.02) days. On the test dataset the system had an accuracy of 91% (31/34) in predicting treatment adequacy and a false positive rate of 9% (3/34). The system recommended change earlier than clinicians in 22/29 cases (76%), with a mean time advantage of 12.5 (2.22) days. CONCLUSIONS: The computer advisory system could improve patient management by reducing the time spent receiving ineffective treatment. This has implications for both patient time and clinical costs.

Biomarkers, Tumor↗
PubMed1992

The cytotoxicity, DNA crosslinking ability and DNA sequence selectivity of the aniline mustards melphalan, chlorambucil and 4-[bis(2-chloroethyl)amino] benzoic acid.

Three aniline derivatives melphalan (L-PAM), chlorambucil (CHL) and 4-[bis(2-chloroethyl)amino] benzoic acid (BAM) have been compared on the basis of their in vitro cytotoxicities, DNA interstrand crosslinking ability and DNA sequence selectivity. Cytotoxicity was assessed in the human colonic adenocarcinoma LS174T and leukaemic K562 cell lines using the sulpho-rhodamine B and tetrazolium dye reduction assays. The order of cytotoxicities was L-PAM greater than CHL greater than BAM in both cell lines with K562 being less sensitive than LS174T. This was different from the order CHL greater than L-PAM greater than BAM which would be predicted from simple chemical reactivity or rate of hydrolysis, parameters which have been used previously as indicators of biological potency for aromatic nitrogen mustards. DNA interstrand crosslinking in cells as determined by alkaline elution showed a correlation with IC50 values. The ranking order of activity was further predicted by the ability of the agents to produce interstrand crosslinks in isolated DNA. The extent of guanine N-7 alkylation, assessed using a modified DNA sequencing technique, mirrored cytotoxicity and crosslinking ability, but at equivalent levels of alkylation there was no significant difference in DNA sequence selectivity. These data demonstrates that simple chemical reactivity or hydrolysis rate is not a good indicator of DNA reactivity or cytotoxicity for a number of aniline mustards, whereas DNA interstrand crosslinking ability either measured directly in cells or in isolated DNA, gives a good indication of biological activity.

4-Aminobenzoic Acid↗
PubMed1992

Gestational and nongestational trophoblastic tumors distinguished by DNA analysis.

In three patients in whom a diagnosis of gestational trophoblastic tumor was possible on the basis of pathology and elevated levels of serum human chorionic gonadotrophin, locus-specific minisatellite probes were used to identify restriction fragment length polymorphisms (RFLP) in DNA from the tumor, the patient, and her partner. On the basis of results from these studies, one tumor, originally diagnosed as a germ cell tumor, was reclassified as a gestational choriocarcinoma, whereas a second tumor, diagnosed as gestational choriocarcinoma, was shown to be of nongestational origin. In the third case, a diagnosis of gestational trophoblastic tumor was confirmed, but in this case the androgenetic origin of the tumor indicated that it was derived, not from the antecedent term pregnancy, but from a previous pregnancy with hydatidiform mole. This study clearly demonstrates the value of DNA analysis in the classification of tumors with trophoblastic differentiation.

Adult↗
PubMed1992

Doppler assessment of the uterine circulation and the clinical behaviour of gestational trophoblastic tumours requiring chemotherapy.

The haemodynamics of the uterine arteries and myometrium were assessed using Doppler ultrasound in forty consecutive patients requiring treatment for invasive mole and choriocarcinoma. The investigations were performed prior to the commencement of chemotherapy and the subjects followed prospectively. The Doppler waveforms from the uterine arteries were analysed using the pulsatility index. It was found that patients with a pulsatility index of 1.1 or less were significantly more likely to develop drug resistance than those with a higher value (P < 0.04). There was no significant association between the pulsatility index and metastatic disease or uterine bleeding. Five out of eight patients who developed drug resistance could have avoided initial inadequate treatment if the Doppler findings were included in the scoring system for selecting chemotherapy for these tumours. It can be concluded that assessment of the uterine arteries using the pulsatility index prior to the treatment of patients with invasive mole and choriocarcinoma is of help in predicting those who will develop drug resistance.

Arteries↗
PubMed1992

Choriocarcinoma. A model for tumour markers.

Human chorionic gonadotrophin (hCG) was the first major tumour marker to be identified and in gestational choriocarcinoma remains the closest we have to the ideal indicator of tumour activity. What is measured in assays for this substance is however a complex subject which has to be understood if misinterpretation of the data is to be avoided. It is also necessary to understand the pathology and natural history of the spectrum of hCG producing tumours. The distinction between luteinising hormone (LH) and hCG only became possible with the production of antisera predominantly directed at the beta subunit of hCG. Since then monoclonal antibodies directed at restricted epitopes have revealed that a range of hCG fragments contribute to what is measured. Within the spectrum of hCG producing lesions are those that are self-terminating whilst others are premalignant, malignant but responsive to chemotherapy, or refractory to all present agents. Awareness of this complexity is essential for interpretation of values. For patients with hydatidiform mole hCG measurements form the basis of identifying progressive lesions and thus constituting a still unique biochemical screening programme for cancer. Its roles in diagnosis, prognostication, monitoring the course of the disease and in follow-up for detection of recurrence are unique in many respects. Although hCG measurements provide information critical to the management of each of these lesions that information can only be properly understood through an understanding of the pathological entities involved and the pharmacokinetics of hCG metabolism and excretion.

Biomarkers, Tumor↗
PubMed1991

Comparison of ondansetron and ondansetron plus dexamethasone as antiemetic prophylaxis during cisplatin-containing chemotherapy.

Ondansetron, a serotonin antagonist, is effective in controlling the emesis associated with cancer chemotherapy; however, emesis in patients receiving high-dose cisplatin is poorly controlled by ondansetron alone. Dexamethasone is an effective antiemetic with no known interaction with serotonin receptors and was thus chosen for study in combination with ondansetron. 31 patients (30 male, 1 female; median age 28.5 years, range 18-49) receiving a 4-day course of a chemotherapy regimen containing cisplatin (100-120 mg/m2) for metastatic germ-cell tumours were entered in a randomised, double-blind, cross-over trial comparing oral ondansetron plus placebo with oral ondansetron plus dexamethasone as antiemetic prophylaxis. Ondansetron (8 mg every 8 h) was given to all patients for 8 days from the start of chemotherapy. Patients were given 8 mg of dexamethasone or placebo every 8 h starting 2 h before cisplatin (on day 4) and continuing for six doses (ie, for 2 days only). A second course of chemotherapy began 14 days after the start of the first, during which patients crossed over to the alternative antiemetic regimen. Results were available from 27 patients. In the 24-48 h after cisplatin 78% of patients taking ondansetron plus dexamethasone reported complete or major control of emesis compared with 30% of those taking ondansetron plus placebo (p = 0.001). Cross-over analysis showed a significant advantage for ondansetron plus dexamethasone in the control of nausea (p = 0.013) and emesis (p less than 0.001) over the 8-day study. 24 of 26 patients expressed a preference for the combination therapy (p less than 0.001). Ondansetron plus dexamethasone is effective antiemetic prophylaxis for high-dose cisplatin chemotherapy, has few side effects, and is active when given orally.

Administration, Oral↗
PubMed1991

Cytotoxicity and activation of CB1954 in a human tumour cell line.

CB1954 (5-aziridin-1-yl-2,4-dinitrobenzamide) is a monofunctional alkylating agent, to which Walker 256 cells are very sensitive. These cells express a nitroreductase which reduces CB1954 to a bifunctional crosslinking agent 5-(aziridin-1-yl)-4-hydroxylamino-2-nitrobenzamide. In vitro testing on the human colon line LS174T showed that the differential cytotoxicities between the monofunctional agent (CB1954), and the active species (generated in situ by the addition of NADH and the Walker rat nitroreductase) were smaller than anticipated due to the unexpected toxicity of CB1954 (IC50 value for CB1954 on LS174T cells of 78 microM). The toxicity of the chemically synthesised active form was less than if it had been generated in situ (on LS174T cells). Further experiments showed that NADH was toxic at the levels used to generate the active species (500 microM). Gel filtration and electrophoresis experiments demonstrated that the human colon carcinoma and choriocarcinoma cell lines MAWI and JAR, as well as LS174T express an enzyme of similar molecular weight to that of the 33 kD Walker cell nitroreductase, which is capable of reducing CB1954 to its toxic metabolite, and reducing MTT to its insoluble formazan salt. The expression of this enzyme presumably accounts for the unexpected toxicity of CB1954.

Animals↗
PubMed1991

A phase-I study of repeated therapy with radiolabelled antibody to carcinoembryonic antigen using intermittent or continuous administration of cyclosporin A to suppress the immune response.

The anti-mouse antibody response was examined in patients receiving repeated i.v. therapy with radiolabelled mouse monoclonal antibody (MAb) to carcinoembryonic antigen (CEA): 131I anti-CEA was given approximately every 2 weeks with cyclosporin A, to suppress the anti-mouse antibody response. Two schedules of cyclosporin A--intermittent therapy for 6 days with each course of anti-CEA and continuous therapy--were compared. Suppression of the immune response in the intermittent high-dose (3 patients) and continuous low-dose groups (4 patients) was equivalent, but the latter regimen was less toxic. Repeated therapy led to the formation of small amounts of anti-mouse antibody, but provided that cyclosporin A was continued it did not prevent further therapy or lead to an increase in the rate of clearance of anti-CEA from blood. Without cyclosporin A no more than 2 courses of antibody therapy could be given. Patients received up to 4 doses of 131I anti-CEA. The nadir platelet count was related to the half-life of 131I anti-CEA in blood. Thrombocytopenia limited the amount of 131I anti-CEA that could be given and determined the interval between treatments. Effective suppression of the anti-antibody response is possible and this study has determined that myelosuppression is the principal obstacle to repeated therapy with radiolabelled antibody.

Adult↗
PubMed1991

The effect of radiosensitizers on radio-immunotherapy, using 131I-labelled anti-CEA antibodies in a human colonic xenograft model.

Anti-CEA antibodies were used for radio-immunotherapy in an established LS174T colonic xenograft in nude mice. A single IV dose of either 131I-PK4S (polyclonal) or -A5B7 (monoclonal) antibody produced tumour regression, and significantly delayed subsequent tumour growth. Administration of a clearing second antibody, 24 hr post 131I-PK4S and at 5 times the dose, significantly reduced the therapeutic effect of radio-antibody alone. Tumours of mice given non-specific antibody or unlabelled anti-CEA antibody grew like those of untreated controls. In an attempt to enhance therapy without increasing dose, radiosensitizers normally employed with external beam radiation were used in combination therapy. When the hypoxic cell radiosensitizer misonidazole was combined with 131I-A5B7, it significantly prolonged tumour-growth inhibition over radio-antibody alone. Conversely, the therapeutic effect of either radio-antibody was significantly reduced when used in combination with the halogenated pyrimidine radiosensitizer 5-iododeoxyuridine. Neither sensitizer alone affected tumour growth.

Animals↗
PubMed1991

Cytoreductive surgery in disseminated non-seminomatous germ cell tumours of testis.

Between 1977 and 1988, 67 patients underwent surgical removal of residual metastatic deposits following an aggressive chemotherapy regimen (cisplatin, vincristine, methotrexate and bleomycin alternating with etoposide, actinomycin D and cyclophosphamide) for disseminated germ cell tumours of the testis (stage IIB or above). Ninety-one surgical procedures were performed. There were 63 (69 per cent) retroperitoneal lymph node dissections, 16 (18 per cent) thoracotomies, three (3 per cent) hepatic resections, three (3 per cent) craniotomies, five (5 per cent) delayed orchidectomies and one anterolateral decompression of the vertebral column. Nine (13 per cent) patients required a repeat retroperitoneal node dissection and one patient needed a repeat thoracotomy to remove recurrent metastatic deposits during the period of follow-up. Multivisceral resections and vascular reconstruction procedures were required in 20 (30 per cent) patients undergoing retroperitoneal node dissection. Fifty-five (82 per cent) patients remain in complete remission with a mean follow-up period of 49.6 months (range 2-121 months). Nine (13 per cent) patients died with metastatic disease between 2 months to 4 years after operation. There were three deaths in the perioperative period (4 per cent). The histology of the resected metastases revealed undifferentiated active tumour in 20 (30 per cent) patients, differentiated mature teratoma in 29 (43 per cent) patients and fibrosis/necrosis in 18 (27 per cent) patients. Twelve (60 per cent) patients with undifferentiated elements and 15 patients (60 per cent) with raised preoperative tumour markers (poor prognostic categories) are in complete remission. Cytoreductive surgery in patients with metastatic germ cell tumours offers the best chance of remission following chemotherapy even in poor prognostic group categories.

Adolescent↗
PubMed1991

Correlation of plasma methotrexate concentration with human chorionic gonadotropin and therapeutic response to low-dose methotrexate-citrovorum factor in low-medium-risk gestational trophoblastic tumors.

Seventeen patients with low- or medium-risk gestational trophoblastic tumors (GTT) and one patient with a placental-site trophoblastic tumor were treated according to an 8-day schedule of low-dose methotrexate (LDMTX) alternating with citrovorum factor (CF). Plasma concentrations of methotrexate (MTX) were correlated with serum human chorionic gonadotropin (hCG) levels and clinical response. After an intramuscular dose of 50 mg, plasma MTX levels rose rapidly, reached a peak concentration of 5.8 x 10(-6) M/liter at 1 hour and persisted above 10(-6) M/liter normally considered inhibitory for DNA synthesis, for approximately 7 1/2 hours. Rapid plasma clearance followed with plasma levels reaching 5-7 x 10(-8) M/liter at the time of CF administration. At 48 hours, plasma MTX levels continued to exceed 10(-8) M/liter--the break point for the appearance of clinical toxicity due to MTX. In six of sixteen, or 38%, an initial rise in hCG levels was observed. Five of the seventeen patients, or 29%, and the one patient with PSTT developed MTX resistance. The administered dose (approximately 30 mg/M2) and plasma pharmacokinetics did not differ significantly between the tumors that responded and became resistant to MTX. The authors conclude that MTX resistance in GTT occurs as a result of impaired cell membrane uptake, gene amplification of dihydrofolate reductase, or both.

Chorionic Gonadotropin↗
PubMed1991

Ablation of human choriocarcinoma xenografts in nude mice by antibody-directed enzyme prodrug therapy (ADEPT) with three novel compounds.

Three novel prodrugs have been designed for use as anticancer agents. Each is a bifunctional alkylating agent which has been protected to form a relatively inactive prodrug. They are designed to be activated to their corresponding alkylating agents at a tumour site by prior administration of an antitumour antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in a two-phase system called antibody-directed enzyme prodrug therapy (ADEPT). The Km and Vmax values for three different antibody-CPG2 conjugates were determined in relation to each prodrug. The Km values ranged from 4.5-12 mumol/l and the Vmax from 0.5-1.6 mumol/U/min. Athymic Nu/Nu mice with palpable transplanted human choriocarcinoma xenografts, which are resistant to conventional chemotherapy, were treated with anti-human chorionic gonadotropin antibodies conjugated to CPG2. This was followed by each of the three novel prodrugs. Significant increase in survival was obtained in three of the regimens tested using only one course of treatment. This demonstrates the potential of a tumour-localised bacterial enzyme to activate protected alkylating agents in order to eradicate an established human xenograft.

Alkylating Agents↗
PubMed1991

Weekly etoposide, methotrexate and actinomycin D, alternating with cyclophosphamide plus vincristine (EMA/CO): a phase II study in advanced gastric carcinoma.

A total of 27 patients with measurable/evaluable metastatic or locally advanced gastric carcinoma were given combination chemotherapy comprising etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA/CO). Ten achieved partial remission, giving a response rate of 37% (95% CI; 21.7%-66.3%), 12 attained stable disease, whereas five had disease progression despite treatment. Drug toxicity was moderate to severe. Five of those who achieved partial remission underwent an attempt to resect residual disease which was successful in only three patients.

Adenocarcinoma↗
PubMed1991

Optimum management of pineal germ cell tumours.

Non-seminomatous pineal region germ cell tumours have a poor prognosis when treated with radiation alone but little is known of the results of treatment with modern chemotherapy. Between 1983 and 1990 five pineal region germ cell tumours presented to the Charing Cross Hospital, London. All five patients received the EpPlt/OMB chemotherapy schedule with escalated dose systemic methotrexate and intra-CSF methotrexate. Two patients had had prior radiotherapy. Four patients (80%) remain well and disease-free 6 months--5 years after completing therapy. Chemotherapy is an effective modality for the treatment of pineal germ cell tumours and should be used when non-seminomatous elements are present or when the placement of ventriculo-peritoneal shunt in the presence of malignant cells in the CSF presents a risk of dissemination.

Adolescent↗
PubMed1991

Results with the EMA/CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine) regimen in high risk gestational trophoblastic tumours, 1979 to 1989.

OBJECTIVE: To assess the efficacy, toxicity and survival in patients with high risk GTT treated with the EMA/CO regimen (etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine/oncovine). DESIGN: Open non-randomized study of 148 consecutive patients referred to the Charing Cross Hospital between 1979 and 1989. SETTING: Trophoblastic disease centre in a London teaching hospital. SUBJECTS: 148 consecutive patients with high risk GTT were treated with the EMA/CO regimen. 76 patients had received no prior chemotherapy and 72 had received prior chemotherapy. MAIN OUTCOME MEASURES: Survival, causes of treatment failure and toxicity were analysed. RESULTS: Of 76 patients who had received no prior chemotherapy, 62 (82%) are in remission; an overall survival of 85% for the 148 patients. Ten of the 76 patients without prior chemotherapy died from extensive disease within 3 weeks of starting chemotherapy. The complete and partial response rates to EMA/CO chemotherapy were 80% and 18% respectively. The addition of cisplatin salvaged 9 of 11 (82%) who developed drug resistance and did not require surgery. Salvage surgery alone resulted in 7 of 8 (87%) having complete remissions. Relapse after EMA/CO chemotherapy is uncommon (5.4%) but survival is still relatively good with further chemotherapy and/or surgery with 6 (75%) of 8 patients obtaining a further sustained remission. Complications from EMA/CO chemotherapy are acceptable with myelosuppression being dose-limiting. Late sequelae are uncommon: menstruation usually returns with a few months, and no fetal abnormalities have been recorded in subsequent pregnancies. One patient developed what we presume to be a therapy-induced acute myeloid leukaemia. CONCLUSION: At present EMA/CO chemotherapy is our treatment of choice for patients with high risk GTT. Its toxicity is predictable and reversible. In patients developing drug resistance, salvage surgery is important. Future developments may include further dose intensification with the addition of haemopoietic growth factors, earlier diagnosis and the separation of gestational from non-gestational trophoblastic tumours.

Adult↗
PubMed1991

Selective uptake of toxic nucleoside (125IUdR) by resistant cancer.

We report uptake of a thymidine analogue 125-Iodine-5-iodo-2'-deoxyuridine (125IUdR) by nude mice bearing human xenografts of choriocarcinoma or colonic cancer. When 125IUdR was given alone, uptake by intestinal tissues was 5-10 times greater than by the tumours as measured by tissue gamma counting. This ratio was reversed when hydroxyurea or cytosine arabinoside were used as inhibitors of ribonucleotide reductase and were given in combination with 5-fluorouracil or methotrexate to inhibit thymidine synthesis shortly before injecting 125IUdR. Counting the radioactivity in tissues removed 24 hours after 125IUdR gave tumour to highest normal tissue ratios of up to 15:1, but the corresponding nuclear grain counts, which is probably a more reliable indicator of selective uptake into DNA, were in excess of 100:1. The addition of unlabelled IUdR to the regimen only reduced the uptake of 125IUdR when given in relatively large amounts. For this approach to be exploited it is concluded that the tumour must be resistant at the cell level to the inhibitor of DNA synthesis either de novo or as a result of prior exposure to it. This inhibitor can then be used to block uptake of the potentially toxic nucleoside analogue by normal renewal tissues while it is taken up by the resistant cancer cells. By inhibiting synthesis of the corresponding normal nucleosides with inhibitors to which the cancer cells are not resistant, incorporation of the toxic analogues into tumour DNA was enhanced. Although 125IUdR is a convenient agent for exploring this approach and is highly cytotoxic when incorporated in DNA, the clinical potential of reverse role chemotherapy probably lies with the development of toxic non-radioactive nucleoside analogues.

Adenocarcinoma↗
PubMed1991

Tissue dose estimates following the selective uptake of 125IUdR and other radiolabelled thymidine precursors in resistant tumours.

For the purposes of evaluation of the therapeutic potential of the radiohalogenated thymidine analogue 125IUdR, estimation of the radiation dose to the tumour cells and normal tissues is important. To determine the dose to any tissue from the radionuclide 125I is not simple, since the major emissions are very short-range Auger electrons. The cytotoxicity of 125I is strongly dependent on the position of the decay relative to the DNA, the principal target for cell sterilization. Estimates of the cytotoxicity of 125I based on the traditional MIRD recommended formulation (ICRU Report 32, 1979) may produce gross underestimates if it is incorporated into the DNA via the thymidine precursor 125IUdR. In this work, tissue count and autoradiography (ARG) data from studies by Bagshawe et al were used to estimate tissue doses following the administration of 125IUdR to LS174/T (a colorectal carcinoma) and CC3 (a choriocarcinoma) tumour-bearing animals, after a hydroxyurea block of the normal tissue turnover. The tumour cell toxicity is estimated from ARG data on the degree of 125I incorporation into the cell nucleus. Major drawbacks with 125I for this type of therapy are the long 60-day half-life, leading to radiological and waste disposal problems and the extreme short range of the radiotoxic effects. Possible alternative radiohalogens, 13I, 77Br, 131I and 211At, are suggested in place of 125I in the thymidine analog iododeoxyuridine. Dose calculations are performed and cytotoxicities estimated on the assumption that their biological retention characteristics are the same as for 125IUdR.

Adenocarcinoma↗