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Biomedical subjects

K D Bagshawe

Publications and source records attributed to K D Bagshawe.

At least 73 records · Page 4Linked to original sources
PubMed1990

Inactivation and clearance of an anti-CEA carboxypeptidase G2 conjugate in blood after localisation in a xenograft model.

Studies with a conjugate of carboxypeptidase G2 (CPG2) and the F(ab')2 fragment of monoclonal anti-CEA antibody, A5B7, have shown specific localisation in a human colon tumour xenograft, LS174T, growing in nude mice. The conjugate reaches a peak concentration in the tumour within 24 h but enzyme activity in blood remains above a critical value for therapeutic purposes for several days. Here we describe a new monoclonal antibody, SB43, raised against CPG2 which is capable of reducing enzyme activity in blood. In vitro studies demonstrated specific binding of SB43 to CPG2 causing inactivation. Moreover, in the nude mouse model SB43 was also capable of inactivating the enzyme in the circulation within minutes of administration. Radiolabelled native SB43 persisted in blood for several days and appreciable non-specific uptake into the xenograft was also observed. Uptake of SB43 by the tumour, with possible inactivation of CPG2 at this site, could be limited by first coupling the antibody to galactose. This ensured recognition and excretion of SB43 and SB43-enzyme complexes via the liver and their rapid removal from the circulation. Galactosylation had no effect on the ability of SB43 to inactivate the enzyme.

Animals↗
PubMed1990

Immunohistological distribution of 5T4 antigen in normal and malignant tissues.

A trophoblast cell surface antigen has been characterised by a monoclonal antibody (mAb) 5T4, raised following immunisation with solubilised wheat germ agglutinin binding glycoproteins from human syncytiotrophoblast plasma membrane (StMPM). The expression of the 72 kDa glycoprotein was assessed on cryostat sections of a range of neoplastic and non-neoplastic tissues, using an avidin-biotin immunoperoxidase technique. In products of conception, intense reactions were noted with villous syncytiotrophoblast membrane in normal early and term placenta, with weaker positivity of placental site trophoblast. Most normal or non-neoplastic tissues were negative, including liver, kidney, spleen, small intestine, ovary and testis. Faint or moderate positive reactions were present in some specialised epithelia. Of 115 neoplasms examined, 76 showed reactions with tumour cells including carcinomas of the bladder, breast, cervix, endometrium, lung, oesophagus, ovary, pancreas, stomach and testicular non-seminomatous germ cell tumours. Choriocarcinomas and placental site trophoblastic tumours were also positive. Most adenocarcinomas of colon and seminomas were negative as were all malignant melanomas and malignant lymphomas. A radioimmunoassay did not detect the antigen in either normal or pregnancy serum. The relatively low level of expression in normal tissues and reactivity with a wide range of carcinomas suggested that the antibody may be useful in diagnostic or targeting studies.

Antigens, Neoplasm↗
PubMed1990

Frequency of serum tumour marker monitoring in patients with non-seminomatous germ cell tumours.

In patients relapsing on surveillance following orchidectomy for stage 1 non-seminomatous germ cell tumours, it is essential that treatment is initiated before they develop advanced disease with a poor prognosis. Patients who start chemotherapy with levels of human chorionic gonadotrophin (HCG) greater than 1,000 i.u. l-1 and/or alpha-fetoprotein (AFP) level greater than 500 ku l-1 have been shown to have a worse prognosis than patients with lower marker levels. We studied 64 patients between 1968 and 1987 with rising serial tumour markers. The potential time in which markers could rise to poor prognostic levels was calculated assuming an exponential rate of increase. Adverse levels were predicted in one patient (1.6%) within 7 days, in two patients (3.1%) within 14 days, in eight patients (12.5%) within 4 weeks and in 16 patients (25%) within 6 weeks. This suggests that, initially, weekly marker estimations should be performed on stage 1 surveillance patients. The extra cost to a specialist follow-up laboratory of weekly as opposed to the usual monthly marker measurements will be less than 33,600 pounds for every 400 patients on surveillance. One extra patient is likely to be cured for this sum.

Biomarkers, Tumor↗
PubMed1990

Preliminary observations on the microdistribution of labelled antibodies in human colonic adenocarcinoma xenografts: relevance to microdosimetry.

Autoradiography with 125I-labelled antibodies 17-1-A and 11-285-14 (anti-carcinoembryonic antigen) injected singly or together into nude mice carrying two distinct human colorectal cancer xenografts delineates marked changes in distribution and retention of isotope over 72 h, which are relevant to microdosimetry. The antibodies localise independently at low concentrations. Slow accumulation and retention predominantly in membranes of glands and necrotic areas suggest that therapy will succeed best with isotopes whose range, half-life and/or mode of delivery can exploit optimally the greater selectivity of the late retention.

Adenocarcinoma↗
PubMed1990

Disposition of the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its active parent drug in mice.

A novel therapy for improving selectivity in cancer chemotherapy aims to modify distribution of a cytotoxic drug by generating it selectively at tumour sites. In this approach an antibody-enzyme conjugate is allowed to localise at the tumour sites before injecting a prodrug which is converted to an active drug specifically by the targeted enzyme in the conjugate. We present here pharmacokinetic studies on the prodrug 4-(bis (2-chloroethyl) amino) benzoyl-L-glutamic acid and its activated derivative, benzoic acid mustard. The glutamic acid is cleaved from the prodrug to form the active drug by carboxypeptidase G2 (CPG2), an enzyme from Pseudomonas sp., which is not found in mammalian cells. The prodrug and its parent active drug were rapidly distributed in plasma and tissues after administration of prodrug or active drug (41 mumol kg-1 intraperitoneally) to mice bearing human choriocarcinoma xenografts. Prodrug and active drug both followed a two-compartment kinetic model. Prodrug was eliminated more rapidly (t1/2 alpha = 0.12 h, t1/2 beta = 0.70 h) than active drug (t1/2 alpha = 0.37 h, t1/2 beta = 1.61 h). Conversion of the prodrug to the activated parent drug was detected within 5 min of administration to mice which had previously received a F(ab')2-anti-human chorionic gonadotrophin antibody (W14A) conjugated to the enzyme, CPG2 (1,000 U kg-1). Tumour was the only tissue that activated all the prodrug reaching the site. It contained the highest concentration of targeted enzyme conjugate capable of catalysing the reaction of prodrug to drug. Plasma and other tissues were also capable of activating the prodrug but active drug production was limited by the amount of enzyme present. The active drug measured in plasma and tissues other than tumour was attributable to residual antibody-enzyme conjugate at non-tumour sites. Low levels of conjugate in tissues and plasma militate against the advantage of tumour localised enzyme therefore necessitating removal of non-localised enzyme.

Animals↗
PubMed1990

The potential of carboxypeptidase G2: antibody conjugates as anti-tumour agents. II. In vivo localising and clearance properties in a choriocarcinoma model.

The in vivo localising and clearance properties of conjugates of the folate-degrading enzyme carboxypeptidase G2 (CPG2) with anti-human chorionic gonadotrophin (W14A) were measured in nude mice bearing CC3 choriocarcinoma xenografts. Conjugates of W14A-F (ab')2 fragment coupled to CPG2 localised in tumour as effectively as native antibody alone but showed lower uptake in other major tissues. The clearance rates of conjugates prepared with intact antibody or F (ab')2 fragment were shown to be up to five-fold faster than for native antibody and two-fold compared to F (ab')2 fragment. Molecular weight analysis of residual conjugate in the blood showed that no degradation of conjugate to its component molecules occurred during circulation. It was concluded that F (ab')2: CPG2 conjugates offered the greatest potential for targeting applications.

Animals↗
PubMed1990

Preliminary Doppler studies on the uterine artery and myometrium in trophoblastic tumours requiring chemotherapy.

The uterine circulation in 38 patients with invasive mole or choriocarcinoma were investigated using Doppler ultrasound. Twenty-six non-pregnant and 23 pregnant volunteers were assessed in a similar fashion to act as control groups. The pulsatility indices were significantly lower in the patients with trophoblastic disease when compared with the non-pregnant and pregnant groups (Student's t-test; P less than 0.001 and P less than 0.02 respectively). The uterine circulation in persistent trophoblastic diseases shows a characteristic Doppler profile suggesting the presence of large low resistance blood vessels. This may be useful in the initial assessment of these tumours before cytotoxic chemotherapy.

Adult↗
PubMed1990

Ultrasonic morphology of the uterus and ovaries after treatment of invasive mole and gestational choriocarcinoma.

Ultrasound imaging of the uterus and ovaries was performed on 41 patients after completion of apparently successful cytotoxic chemotherapy for invasive mole and choriocarcinoma. Uterine volume was calculated and the echopattern of the uterus and ovaries assessed. Forty-nine per cent of subjects had an abnormal uterine appearance and 20% had ovarian theca-lutein cysts. Two patients relapsed on follow-up but no predictive ultrasonic features could be established on uterine or ovarian morphology after chemotherapy.

Antineoplastic Agents↗
PubMed1989

Characterisation of antibodies to urinary gonadotrophin peptide.

There is now general recognition that human chorionic gonadotropin (hCG), its beta subunit and its fragments are valuable diagnostic markers of trophoblastic and some non-trophoblastic malignancies. Urinary gonadotropin peptide (UGP) contains at least one epitope which cross-reacts with the beta-subunit of hCG. In order to assess the potential of UGP as a tumour marker in its own right, it was paramount that any measurements made could be regarded as specific for UGP and not cross-reactive with either hCG or human luteinising hormone (hLH). Four antibodies were tested, two polyclonal (AK12 and DR-Pool) and two monoclonal (2C2 and 6D3). Initial screening using radioiodinated (125I) UGP, hCG, hCG beta-subunit and hLH showed that the polyclonal antibodies bound to all four gonadotrophins, whilst the monoclonal antibodies bound only to the radioiodinated UGP. The antibodies were tested in both radioimmunoassay (RIA) and immunoradiometric assay (IRMA-sandwich assay) systems. The parameters measured were sensitivity and specificity for UGP. The polyclonal antibodies used in the RIA system produced a sensitive assay (0.2 ng/ml UGP) which was relatively specific; cross-reactions for the AK12 antibody (at 50% inhibition) were 5% for hCG, 11% for its beta-subunit, 0.4% for the alpha-subunit and 2.6% for hLH. The monoclonal antibodies performed optimally in the IRMA system. Immobilised 2C2 and radiolabelled (125I) AK12 produced a system that had a sensitivity of 0.4 ng/ml UGP and cross-reactivity (50% maximum binding) of 2% for the hCG beta-subunit and less than 1% for hCG, hLH and the hCG alpha-subunit.

Antibody Specificity↗
PubMed1989

Treatment of small cell lung cancer by eight weeks chemotherapy.

Eighty-two patients with small cell lung cancer (SCLC), 32 with limited disease, were treated with alternating chemotherapy. Eight courses were administered at weekly intervals, and responding patients received radiotherapy to sites of bulk disease. Overall response rate was 76.8%. Overall median survival was 265 days, 408 days in patients with limited disease. The median symptom free period after chemotherapy was completed was 123 days. These results are comparable with those in reports of chemotherapy of longer duration and warrant the further investigation of short duration treatment in this disease.

Adult↗
PubMed1989

EMOP/CA chemotherapy for the treatment of aggressive non-Hodgkin's lymphomas.

From October 1983 to June 1987, 32 patients with aggressive non-Hodgkin's lymphomas (diffuse centroblastic, lymphoblastic and Burkitt type) were treated with the weekly alternating EMOP/CA schedule, total duration 12 weeks. There were six bulky stage II, nine stage III and 17 stage IV patients, median age 54 years (range 19-75). The complete remission rate was 59% (95% confidence limits 40-76%) and the partial remission rate 28% providing an overall response rate of 87%. With a median follow up time of 33 months (range 18-56) the relapse-free survival of those patients achieving a complete remission is 52% and the overall survival for the 32 patients treated is 27%. The CR rate for patients with stage IV disease was 47% and for those with stage II and III disease was 73% of whom 81% remain in remission. EMOP/CA chemotherapy produces acceptable results in stage II and III aggressive non-Hodgkin's lymphomas but is inadequate therapy for stage IV disease.

Adult↗
PubMed1989

The First Bagshawe lecture. Towards generating cytotoxic agents at cancer sites.

Several years of experience have now accumulated in the targeting of anti-cancer agents so that we can take stock, identify problems and look for ways round them. Three major obstacles seem to limit present approaches. These are heterogeneity in the distribution of target molecules within the cancer cell population, the pharmacokinetic characteristics of macromolecules and host antibody response to foreign protein. An approach which we have been investigating uses antibodies or other vectors to carry enzymes which have no close human homologue to tumour sites. After clearing residual enzyme activity from the blood by one of several possible techniques, a relatively non-toxic prodrug is given. This prodrug is a substrate for the tumour located enzyme which results in the generation of a highly toxic molecule able to penetrate the tumour mass and cross cell membranes. Genetic engineering methods now offer the prospect of human immunoglobulins with tumour binding and catalytic sites having the potential to minimise host response. Whether this can be achieved depends on having antibodies with adequate specificity and our ability to develop enzyme-prodrug systems with the required characteristics. Early results encourage us to think progress can be made in this direction.

Antineoplastic Agents↗
PubMed1989

Antibody distribution and dosimetry in patients receiving radiolabelled antibody therapy for colorectal cancer.

The distribution of iodine-131 (131I) labelled antibody to carcinoembryonic antigen (CEA) has been studied in 16 patients with colorectal cancer. Levels of tumour and normal tissue radioactivity were measured by serial gamma-camera imaging and counting of blood and urine. Maximum concentrations were found in tumour 8 h after administration and varied up to 9-fold in different patients. Higher levels were found on average in tumour than in any other tissue. Liver, lung and blood were the other tissues in which antibody was concentrated relative to the rest of the body. Antibody cleared from all these tissues over 1 week. Second antibody directed against the antitumour (first) antibody was given 24 h after first antibody in order to accelerate clearance from the blood. This increased the tumour to blood ratio but had little effect on other tissues. Cumulative radiation dose to tumour and normal tissue was estimated. In patients with the most efficient localisation the tumour to body ratio was 20:1 and tumour to blood ratio 5:1. This may be sufficient for effective therapy of cancer in patients selected for efficient antibody localisation. The data may be used to estimate the effect of different therapeutic strategies. For instance, in the time after second antibody administration the average tumour to blood ratio of radiation dose was 11:1, suggesting that two phase systems in which the therapeutic modality is given after a good tumour to normal tissue ratio is obtained may be effective for the majority of patients.

Antibodies, Neoplasm↗
PubMed1989

The effect of serum CEA on the distribution and clearance of anti-CEA antibody in a pancreatic tumour xenograft model.

A human pancreatic adenocarcinoma was used to develop two histologically distinct xenograft lines, one associated with high levels (180-2000 ng ml-1) and one with low levels (greater than 2.0 less than 8.0 ng ml-1) of serum carcinoembryonic antigen (CEA). A strong correlation was found between tumour size and both circulating and tumour CEA levels in the former group, and also correlation at the 5% level between tumour size and serum CEA in the latter. Administration of either monoclonal or polyclonal 125I-anti-CEA antibody led to the formation of intravascular antigen-antibody immune complexes in mice with high CEA levels, and these were rapidly cleared by the liver, deiodination commencing within the first hour. Blood activity was reduced to 20% of the injected dose by 15 min, and by 24 h the radioactivity in all tissues except muscle was significantly below that found in either the low CEA group or in mice without tumours. No difference in radio-antibody clearance pattern was found between mice without tumours and the group with low levels of serum CEA. In spite of higher levels of CEA within the tumour in mice with elevated serum CEA, the rapid clearance of antigen-antibody complexes reduced tumour localisation to one quarter of that seen in mice with low serum, and correspondingly low tumour, CEA levels. Gamma-camera imaging confirmed these results. Possible implications to patient selection and treatment are discussed.

Adenocarcinoma↗
PubMed1989

Long-term outcome in patients with germ cell tumours treated with POMB/ACE chemotherapy: comparison of commonly used classification systems of good and poor prognosis.

We analysed outcome in 206 consecutive male patients treated for metastatic non-seminomatous germ cell tumour (NSGCT) of testicular or extragonadal origin treated with the POMB/ACE (cisplatin, vincristine, methotrexate, bleomycin, actinomycin D, cyclophosphamide, etoposide) regimen after division into prognostic groups by commonly used clinical classification systems and definitions of adverse prognosis. The adverse prognostic groups of all classification systems and definitions examined showed similar, but only moderate, sensitivity (71-81%) and specificity (52-56%) in predicting death. A simple definition of poor prognosis based on raised initial levels of serum tumour markers alpha fetoprotein (aFP) and human chorionic gonadotrophin (hCG) proved at least as useful (sensitivity 80%, specificity 55%) as other more complicated systems in predicting failure to achieve long-term survival. Comparison of survival between ultra-high dose cisplatin-based combination chemotherapy and patients treated with POMB/ACE shows no advantage from this more toxic approach. This suggests that good results in adverse prognosis patients can be achieved using conventional dose regimens administered intensively.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

The effect of intensity of administered treatment on the outcome of germ cell tumours treated with POMB/ACE chemotherapy.

In order to assess the importance of the intensity of administration of chemotherapy in the management of advanced germ cell tumours we have calculated indices of chemotherapy. These have been used to compare the treatment given to patients who subsequently relapsed with matched controls who did not relapse. Two of these indices (alpha and beta) are derived from the doses of drugs whose dose is varied (cisplatinum, methotrexate and etoposide). These indices showed significant variation between cases and controls. Indices gamma and delta are derived from drugs whose dose is not varied. They showed no significant differences between the two groups. These results emphasise the importance of ensuring that patients with these curable cancers receive adequate doses of chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗