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Biomedical subjects

A A Epenetos

Publications and source records attributed to A A Epenetos.

At least 19 recordsLinked to original sources
PubMed2001

Radioimmunoscintigraphy in patients with ovarian cancer.

The use of radiolabeled monoclonal antibodies (MoAbs) has significantly improved the ability to detect tumor antigens, thus improving in vivo tumor diagnosis and treatment. The management of ovarian carcinoma still poses a challenging medical problem. Clinical trials using radioimmunoscintigraphy or a hand-held gamma detection probe intraoperatively were performed in patients with clinical evidence of primary or recurrent ovarian cancer. Immunoscintigraphy of ovarian cancer lesions has been performed mainly with 99mTc, 111In and 123I labeled with HMFG1, HMFG2, OC-125, B72.3, H17E2, OVTL3, MoAb170, Mov18 and other MoAbs. Antibody guided imaging using radioimmunoscintigraphy has demonstrated improved targeting of ovarian cancer, resulting in a highly sensitive and specific method. However, it is not yet known which type of MoAb is the most efficient for radioimmunoscintigraphy. Since these tumors represent a potentially curable disease, radioimmunoscintigraphy could contribute mainly to accurate staging as a supplementary to conventional diagnostic methods, as well as for the localization of active disease after chemotherapy and monitoring for the presence of recurrent disease. Nevertheless, prospective studies in a large number of patients should be undertaken in order to further evaluate the diagnostic contribution of this approach.

Antibodies, Monoclonal↗
PubMed2000

A recombinant cytotoxic chimera based on mammalian deoxyribonuclease-I.

A number of mammalian proteins with suitable biological activities have been considered for use in targeted tumour therapy. Deoxyribonuclease-I (DNase-I), an endonuclease that degrades double-stranded DNA, represents an attractive candidate for tumour targeting since it is normally non-toxic yet could be highly cytotoxic when redirected to the cell nucleus. Our aim was to investigate the cytotoxic potential of mammalian DNase-I and its possible use in tumour-targeting strategies for cancer therapy. A chimeric molecule comprising a scFv reactive against the human placental alkaline phosphatase (hPLAP) and bovine pancreatic DNase-I was designed and investigated. The development of a tightly controlled system for the bacterial expression of DNase-I and its chimera is described. The production and purification of active DNase-I from the soluble cell fraction and significant yields from the insoluble fraction by isolation and refolding are described. The construction, expression, purification and in vitro characterisation of an anti-PLAP scFv-DNase-I chimera is also described. This molecule was shown to possess both antigen-binding and DNA-degrading activity in in vitro assays, thus combining the specific cell-targeting properties of the scFv and the potent, highly catalytic activity of the endonuclease. Furthermore, this chimeric molecule was highly cytotoxic in vitro in cells expressing the PLAP antigen. Targeting mammalian DNase-I provides a novel therapeutic strategy for selective cell killing, with the promise of less systemic toxicity and immunogenicity than currently used immunotoxins.

Alkaline Phosphatase↗
PubMed1999

Development of a novel bi-specific monoclonal antibody approach for tumour targeting.

To overcome the disadvantages of bi-specific antibody methodologies in vivo, a novel antibody approach has been designed to improve tumour targeting and effector to target ratio. The technique involves biotinylated anti-CD3 Fab fragments and streptavidinylated anti-tumour monoclonal antibodies (mAbs) that can spontaneously form cross-links. We describe here a method for the direct cross-linking of sulphydryl-conjugated HMFG1 (anti-MUC1 mucin mAb) to streptavidin by sulphosuccinimidyl-4-(N-maleimidomethyl) cyclohexane-1-carboxylate. Fab fragments generated by papain digestion of the 1452C11 antibody (anti-CD3 mAb without Fc to avoid peripheral activation of T-cells) were biotinylated with NHS-Iminobiotin. MUC1-transfected BALB/c breast cancer cell lines 413BCR and 425CCR and the parental cell line (410.4) were labelled with streptavidinylated mouse anti-MUC1 mucin mAb. BALB/c effector T-cells were separately labelled with biotinylated anti-CD3 Fab fragments (1452C11) and mixed with tumour cells in different effector to target ratios. Percentage of killing was assessed using the 51Cr cytotoxicity assay. Seventy per cent lysis was measured in the case of 413BCR (high MUC1 mucin expressor) and 40% in the case of 425CCR (low expressor) cell line. No lysis was apparent in the MUC1 negative cell line. These results demonstrate that the novel T-cell redirecting approach we have developed can produce effective immune lysis of target cells in vitro.

Animals↗
PubMed1999

Radioimmunoscintigraphy in patients with ovarian cancer.

The targeting potential of three different monoclonal antibodies (MAbs) was assessed in patients with ovarian cancer. HMFG1, OC-125 and H17E2 labelled with 111In or 123I were evaluated prospectively for their ability to localize ovarian tumour. Forty two patients with ovarian cancer, aged 40-78 years (median = 58 years) were studied using OC-125 (n = 9), HMFG1 (n = 11) and H17E2 (n = 22). Imaging data were compared with the CT and the surgical findings. Presence of tumour was confirmed in 35/42 (83%) patients (8/9 OC-125, 10/11 HMFG1 and 17/22 H17E2) and correlated well with the conventional radiology diagnostic methods. One patient with a negative H17E2 scan and a large abdominal mass detected at laparotomy revealed a PLAP-negative tumour on immunohistochemistry. Scintigraphy revealed the presence of active disease, confirmed by laparotomy/laparoscopy in 6/8 patients considered to be in clinical remission. The sensitivity of the method was high enough and the diagnostic contribution of this approach should be further evaluated.

Adult↗
PubMed1999

Intravesical administration of radiolabelled tumour-associated monoclonal antibody in bladder cancer.

Considerable progress has been made over the past decade in the use of tumour-associated monoclonal antibodies (mAbs) as carriers of cytotoxic agents in the management of several malignancies. In the present study we investigated the tumour localization and biodistribution of the mAb HMFG1 to bladder cancer following intravesical administration. HMFG1, which has been raised against the polymorphic epithelial mucin (PEM), was labelled with 125I and administered intravesically 2 h and 24 h before cystoscopy. During cystoscopy, biopsies were taken from the normal bladder and the malignant lesion. Tissue samples were tested for HMFG1 immunostaining and for radioactivity with the use of a gamma-counter. The mean ratio of tumour to normal uptake for 125I-HMFG1 was 5.81 +/- 1.23, at 2 h and 2.17 +/- 0.42 at 24 h. No radioactivity was detected in the blood. We conclude that HMFG1 could be used intravesically for the successful delivery of a cytotoxic agent.

Administration, Intravesical↗
PubMed1999

Use of monoclonal antibodies for the diagnosis and treatment of bladder cancer.

Although the management of cancer by exploiting properties distinguishing neoplastic and normal cells has always been an attractive concept, it was the development of hybridoma technology and the resulting tumor-associated monoclonal antibodies (MAbs) that offered new prospects for this strategy. Twenty years later, some of the applications of MAbs in oncology are now part of the everyday diagnosis and treatment, while others are the subject of intensive investigation. We reviewed the current applications of MAbs in the diagnosis and treatment of bladder cancer and attempted to put the issue into perspective, with particular presentation of their therapeutic potential.

Animals↗
PubMed1998

In vitro cytotoxicity following specific activation of amygdalin by beta-glucosidase conjugated to a bladder cancer-associated monoclonal antibody.

We describe a novel version of antibody-directed enzyme prodrug therapy (ADEPT), with the use of amygdalin as prodrug. Amygdalin is a naturally occurring cyanogenic glycoside, which can be cleaved by sweet almond beta-glucosidase to yield free cyanide. If amygdalin could be activated specifically at the tumour site, then malignant cells would be killed without the systemic toxicity usually associated with chemotherapy. To this end, we have conjugated beta-glucosidase to a tumour-associated monoclonal antibody (MAb) (HMFG1) and the conjugate has been tested in vitro for specificity and cytotoxicity subsequent to activation of amygdalin. Amygdalin was cytotoxic to HT1376 bladder cancer cells only at high concentrations, whereas the combination of amygdalin with HMFG1-beta-glucosidase enhanced the cytotoxic effect of amygdalin by 36-fold. When 2 concentrations of HMFG1-beta-glucosidase were compared, the toxic effect was dose dependent. The cytotoxicity of amygdalin was also enhanced by the MAb-enzyme conjugate even when the unbound conjugate was removed from the medium prior to exposure to amygdalin and the cells were washed. In addition to the cytotoxic effect, we also demonstrated specificity, using a MAb-enzyme conjugate that does not recognise the HT1376 bladder cancer cells. Finally, we studied the cytotoxic effect of the conjugate in co-culture of HMFG1-positive and-negative cell lines (HT 1376 and U87MG cells). We demonstrated that the rate of surviving cells corresponds well to the percentage of U87MG (HMFG1-negative) cells in the flask. Our findings indicate that ADEPT is more effective than non-directed enzyme activation of a prodrug and can result in a non-toxic cancer therapy.

Amygdalin↗
PubMed1998

Improving tumour targeting and decreasing normal tissue uptake by optimizing the stoichiometry of a two-step biotinylated-antibody/streptavidin-based targeting strategy: studies in a nude mouse xenograft model.

We aimed to study in detail the in vivo stoichiometry of the individual elements of the 2-step streptavidin based approach to tumour targeting, in a nude mouse xenograft model, by the administration of a first step consisting of biotinylated anti-tumour specific antibody and a second step consisting of streptavidin. This process was undertaken to identify the optimum conditions for radiotherapeutic tumour targeting using this approach. Antibody was biotinylated to various degrees (1-25 biotins per antibody). Protein stoichiometry of the 2 steps was studied over a range of 2 logs. Both steps, i.e., the biotinylated-antibody (1st step) and streptavidin (2nd step) were radiolabelled (125I and 131I, respectively). A 24-hr interval between 1st and 2nd step was studied, animals being killed 24 hr after the 2nd step. Streptavidin excess led to a decrease in levels of monobiotinylated-antibody in the circulation and in the tumour. Biotinylated-antibody excess led to an increase in circulating levels of streptavidin, a decrease in renal uptake of streptavidin and increased targeting of streptavidin to tumour. At a constant protein molar ratio of biotinylated antibody to streptavidin of 10:1, increasing biotinylation density resulted in an increase in circulating levels, increase in tumour uptake, decrease in renal uptake and increase in liver uptake of streptavidin. As early as 24 hr, the tumour-to-blood ratios of streptavidin already exceeded 1 (max 1.27). Compared with antibody tumour-to-blood ratios, they were better by a factor of between 2 and 3. Tumour-to-normal tissue ratios of radiolabelled streptavidin (with the exception of liver) were also significantly improved when polybiotinylated-antibody was administered first. We have thus shown that the 2-step biotinylated antibody/streptavidin approach can lead to a significant increase in absolute amounts of activity in the tumour under appropriate stoichiometric conditions. This was accompanied by high levels of circulating streptavidin and relatively favourable tumour-to-blood and normal tissue ratios of streptavidin.

Animals↗
PubMed1998

Imaging of metastatic melanoma utilising a technetium-99m labelled RGD-containing synthetic peptide.

Integrins are cell-surface glycoproteins found in different forms on all cells except erythrocytes. Integrins bind to cell adhesion molecules and to proteins found in the extracellular matrix. A tripeptidic sequence Arg-Gly-Asp (RGD) is often the primary site of recognition by integrins which are expressed on tumour cells and are responsible for tumour invasion and metastasis. A synthetic decapeptide designated alpha P2 containing two RGD sequences radiolabelled with technetium-99m was used to image malignant melanoma in vivo. Fourteen patients previously diagnosed with metastatic melanoma underwent gamma camera imaging 20-180 min following intravenous administration of the radiolabelled synthetic decapeptide alpha P2. Six out of eight (6/8) of the lymph node metastases (75%) and all other neoplastic sites (11 sites) were successfully imaged, with the exception of three sites in the mediastinal area which were not positively imaged. In two cases there was false positive uptake in the rounded pigmented areolar/nipple area. In three cases (seven sites) the peptide scan confirmed the absence of disease in suspected lesions (true-negative). The synthetic peptide was rapidly removed from the circulation by filtration through the kidneys and excretion in the urine. No toxicity or adverse events were recorded. Radiolabelled alpha P2 peptide, which binds specifically to adhesion molecules on tumours, can be used for the in vivo detection of neoplastic metastases.

Adult↗
PubMed1998

Design, characterization and anti-tumour cytotoxicity of a panel of recombinant, mammalian ribonuclease-based immunotoxins.

Bovine seminal ribonuclease (BSRNase) is an unusual member of the ribonuclease superfamily, because of its remarkable anti-tumour and immunosuppressive properties. We describe here the construction, expression, purification and characterization of a panel of six immunotoxins based upon this enzyme and show that we can increase its anti-tumour activity by over 2 x 10(4)-fold. This is achieved by improving tumour cell targeting using a single-chain Fv (scFv) directed against the oncofetal antigen placental alkaline phosphatase. As well as the simple scFv-BSRNase fusion protein, we have constructed five other derivatives with additional peptides designed to improve folding and intracellular trafficking and delivery. We find that the molecule most cytotoxic to antigen (PLAP)-positive cells in vitro is one that contains a C-terminal 'KDEL' endoplasmic reticulum retention signal and a peptide sequence derived from diphtheria toxin. All these molecules are produced in Escherichia coli (E. coli) as insoluble inclusion bodies and require extensive in vitro processing to recover antigen binding and ribonuclease activity. Despite incomplete ribonuclease activity and quaternary assembly, these molecules are promising reagents for specific chemotherapy of cancer and are potentially less harmful and immunogenic than current immunotoxins.

Alkaline Phosphatase↗
PubMed1997

A pilot pharmacokinetic and immunoscintigraphic study with the technetium-99m-labeled monoclonal antibody BC-1 directed against oncofetal fibronectin in patients with brain tumors.

BACKGROUND: Preliminary experiments in an animal model have shown the favorable tumor targeting potential in vivo of radiolabeled BC-1, an immunoglobulin (Ig)G1 monoclonal antibody (MoAb) that recognizes the human fibronectin isoform (B+) containing the ED-B oncofetal domain. This antigen has extremely restricted distribution in normal adult tissues. Instead, it is highly expressed in fetal and tumor tissues, especially in high grade astrocytomas and malignant gliomas of the brain, in which the process of neoangiogenesis linked to tumor growth is particularly important. METHODS: This study was carried out with five patients who had malignant brain tumors (four gliomas and one malignant angioblastic meningioma). The BC-1 MoAb was labeled with technetium-99m (99mTc) by MDP transchelation. Planar and single photon emission computed tomography (SPECT) imaging was acquired at 4-6 and 20 hours after intravenous injection of about 450 MBq/0.2 mg 99mTc-BC-1 and was compared with the nonspecific indicator of blood-brain barrier disruption, 99mTc-diethylenetriamine pentaacetic acid (DTPA). Plasma pharmacokinetic analysis was based on serial blood sampling. All patients underwent potentially curative surgery at the end of the study. RESULTS: The plasma clearance curves were biexponential, with average T(1/2) values of 2-4 hours and 28-33 hours, respectively. 99mTc-BC-1 showed very low nonspecific uptake in the bone marrow, liver, and spleen. Planar and SPECT imaging with 99mTc-BC-1 visualized brain tumors in all patients, with a pattern of intratumor distribution that specifically identified areas of peripheral tumor growth more accurately than the nonspecific indicator, 99mTc-DTPA. Tumor uptake of 99mTc-BC-1 was correlated with the expression of the specific oncofetal fibronectin, as shown by immunohistochemistry on surgical samples. CONCLUSIONS: These results indicate the diagnostic potential of MoAb 99mTc-BC-1 for immunoscintigraphy in cancer patients, at least when neoangiogenesis induced by cancer is particularly important.

Adult↗
PubMed1997

Redesigned anti-human placental alkaline phosphatase single-chain Fv: soluble expression, characterization and in vivo tumour targeting.

Although much progress has been made in the production of recombinant antibodies and their fusions, there are still problems with solubility and folding. Useful antibodies produced from cloned hybridomas do not always result in scFvs behaving favourably. We report here further work on an scFv (H17E2) against the oncofetal antigen human placental alkaline phosphatase. The overall expression was greatly improved and the H17E2 scFv was redesigned by manipulation of the interdomain linker, resulting in much higher expression levels of the soluble scFv in its active conformation at 0.2-0.5 mg/l of bacterial culture. We show that the new soluble version of this scFv has similar characteristics to the refolded version in terms of antigen and tumour cell binding, stability and in vivo pharmacokinetics. The final tumour uptake behaviour of these scFvs is superior to that of the parental whole antibody with respect to tumour:organ ratios, but still requires further development before considering it as a suitable molecule for clinical use in ovarian or testicular cancer.

Alkaline Phosphatase↗
PubMed1996

Enhanced in vivo immunogenicity induced by an antibody to the IL-4 receptor-associated gp200-MR6 molecule.

Four murine IgG1 monoclonal antibodies, each with specificity for a human tumour-associated antigen, have been tested for their in vivo immunogenicity using a rabbit model. Surprisingly, one of these antibodies, MR6, was significantly more immunogenic than the remaining three reagents. This enhanced MR6 immunogenicity was not restricted to the immunoglobulin molecule itself, but also applied to a hapten (fluorescein isothiocyanate, FITC) when conjugated to the monoclonal antibody. In addition, the secondary immune response to an independent antigen, human haemoglobin, was higher when the antigen was administered simultaneously with MR6 than when co-injected with an isotype-matched control monoclonal antibody. The presence of the target antigen, gp200-MR6, on both rabbit and human leucocytes and epithelium, and its known association with human IL-4 function, raises the possibility that antibody MR6 may not only target immunogens to antigen-presenting cells, but may also enhance the ability of these cells to present antigen to the immune system. Antibodies to the gp200-MR6 may therefore find important clinical application as in vivo adjuvants.

Animals↗
PubMed1995

E-cadherin expression in bladder cancer using formalin-fixed, paraffin-embedded tissues: correlation with histopathological grade, tumour stage and survival.

To determine the potential prognostic value of epithelial cadherin (E-cadherin), a Ca(2+)-dependent cell-cell adhesion molecule, we have analysed its immunoreactivity and cellular localisation in 67 transitional cell carcinomas (TCC) using an avidin-biotin immunoperoxidase technique on formalin-fixed, paraffin-embedded tissues. These results were correlated with histopathological grade, tumour stage, presence of metastases and survival. In addition, 10 cystitis and 11 normal bladder biopsies were evaluated as controls. E-cadherin was expressed in a normal membranous pattern in all normal and 7 of 10 cystitis biopsies. Loss of normal surface E-cadherin expression was found in 3 of 15 superficial tumours and in 48 of 52 invasive cancers. Abnormal immunoreactivity was strictly related to tumour differentiation and stage. Fifteen of 20 well-differentiated (grade I) tumours showed preserved membranous E-cadherin immunoreactivity, while 46 of 47 moderate and poorly differentiated tumours (grades II and III) demonstrated abnormal staining patterns. Loss of membranous E-cadherin immunoreactivity was also associated with advanced tumour stage. There was a significantly higher 5-year survival rate for patients with preserved membranous staining compared with patients with abnormal staining.

Cadherins↗
PubMed1995

Radiolabeled antibody combined with external radiotherapy for the treatment of head and neck cancer: reconstruction of a theoretical phantom of the larynx for radiation dose calculation to local tissues.

We propose to use radiolabeled antibodies in combination with external beam radiotherapy to improve locoregional control of head and neck cancer. In this case radiation toxicity to mucosa may become a dose-limiting factor and a calculation of the possible compensatory decrease to the external beam radiotherapy would be needed. For this purpose, the following theoretical phantom of a representative organ of this anatomic region, the larynx, was reconstructed and local dosimetric data were derived for a selection of beta-emitting isotopes. The phantom was reconstructed as cylindrical concentric tubes using the established values of an outer diameter of 38 mm and a height of 44 mm. Published mean adult larynx weight (28 g) and cartilage weight (14.7 g) were used. Mean mucosa weight from 5 mucosa samples of our patients was calculated to be 2.0 +/- 0.4 (SD) g. The remaining weight was apportioned to a fat/muscle compartment (11.3 g). The specific gravity of cartilage (1.10 g/cm3), mucosa (1.04 g/cm3), and fat/muscle (1.04 g/cm3) were used to cross-check the volume/mass disparity of the theoretical tubular tissue shells. The established maximum glottic diameter of 24 mm was used to calculate the central air column volume. Mean laryngeal tumor volume from 8 representative laryngeal tumors was 4.4 +/- 3.1 cm3. Tissue compartment thickness was 660 microns for mucosa, 3100 microns for muscle/fat, and 3320 microns for cartilage. These values allowed the calculation of dose absorbed fractions for a number of theoretical radioimmunoconjugates by extending the established calculation of absorbed fractions for spheres of known diameter to absorbed fractions of tissue planes (annuli) of known thickness. We calculated a Deq for the respective tissues in the larynx for 131I-, 186Re-, 188Re-, 67Cu-, 90Y-, and 153Sm-labeled HMFG1. Compensatory decrease to the external radiotherapy dose is 1.1 Gy for each injection of the radioimmunoconjugate we propose to use (131I-HMFG1). This would be best implemented through the modification of the external radiotherapy fractions falling within 2 effective half-lives of this radioconjugate in the mucosa.

Aged↗
PubMed1995

Pharmacokinetics, biodistribution, and dosimetry of specific and control radiolabeled monoclonal antibodies in patients with primary head and neck squamous cell carcinoma.

The pharmacokinetics, biodistribution, and dosimetry of an IgG1 radiolabeled anti-mucin mAb (HMFG1) and an isotype-matched control (4D513) were studied in 29 patients with primary head and neck squamous cell carcinoma. Patients were given injections at 3 fixed time points prior to surgery, i.e., 24 (n = 12), 48 (n = 9), or 72 (n = 8) h. They were subsequently classified into two groups based on their immunohistochemical positivity for polymorphic epithelial mucin. Fourteen patients (48%) were positive, 5 of which were studied with both antibodies; and 15 patients were negative (52%), 7 of which were studied with both antibodies. There was no significant difference in serum pharmacokinetics and cumulative urinary clearance of the two antibodies. There was no significant difference in overall normal tissue uptake of specific and control antibody; however, when each component of the normal tissue category was analyzed individually, there was a significantly increased uptake of HMFG1 in mucosa as compared to control antibody. Immunohistochemical studies revealed positive staining of mucosa with HMFG1. There was significantly increased uptake of specific antibody in antigen-positive tumors as compared to uptake of control antibody (P < 0.02). A tendency for less label loss over time from positive tumors as compared to control was documented. Absolute antibody uptake and tumor/normal tissue ratios demonstrated significant overlap in individual patients from each category depending on the specific ratio (e.g., tumor/adipose tissue) or time point studied; hence arbitrary cutoff values could not be recommended as indicators of specific uptake. Specificity and localization indices were the most reproducible indicators of specific localization. Areas under the curve were calculated for all tissues, and local dosimetry for the two beta-emitting isotopes 131I and 90Y is presented. The Deq values for antigen-positive tumors were 2.9 cGy/mCi for 131I and 9.0 cGy/mCi injected for 90Y. For antigen-negative tumors these values were significantly lower at 0.83 and 2.4 cGy/mCi of 131I and 90Y, respectively. Bone marrow Deq was calculated to be 0.87 cGy/mCi of 131I-HMFG1 injected. Because the purpose of our ongoing research is to assess the therapeutic potential of the combination of radiolabeled antibody and external radiotherapy, detailed dose calculation to local dose-limiting tissues is required. Deq to mucosa was calculated to be 1.1 and 3.8 cGy/mCi of injected 131I and 90Y, respectively. We conclude that a 9-10-Gy dose increment may be achieved in two administrations of 150 mCi of 131I-HMFG1 during a course of external radiotherapy. This may lead to improved control of local disease in patients with head and neck cancer.

Adult↗
PubMed1995

Effect of tumour necrosis factor on the uptake of specific and control monoclonal antibodies in a human tumour xenograft model.

The investigations reported in this paper aim to exploit tumour necrosis factor (TNF)-induced vascular changes in an attempt to increase the tumour uptake of specific monoclonal antibody. The vascular permeability to monoclonal antibody of a human tumour xenograft increased 2.6-fold by 1 h post injection of 2.5 x 10(3) U of TNF, although this effect was lost by 3 h. The normal tissues also demonstrated increased vascular permeability to IgG, but to a lesser extent. Liver permeability increased 1.5-fold at 1 h but returned to the control value by 6 h. Lung permeability increased 1.4-fold at 1 h post injection and returned to normal by 3 h. Muscle values were not significantly increased compared with controls. The blood activity was cleared more quickly in the TNF-treated mice (t1/2 beta = 101 h, compared with 121 h in control mice). This was probably due to the increased vascular permeability in normal organs of treated mice. At 1 day and 3 days post injection, the tumour uptake of the specific, but not the control, antibody was significantly increased by 25% and 29% respectively. This resulted in an increase in the area under the tumour activity curve, and therefore tumour radiation dose, of 25% in treated compared with control mice. In addition, a consequence of the faster blood clearance of the isotope in the TNF-treated mice was a reduction in the area under the blood activity curve of 12%, thereby reducing systemic toxicity. The increase in vascular permeability to IgG following TNF injection resulted in both specific and control antibodies having improved access to the tumour antigens, and a transient increase in uptake was observed. Only in the case of the specific antibody was the increase maintained, since this antibody binds to the available antigenic sites, whereas the control antibody was cleared from the tumour without binding. No evidence of tumour necrosis was observed at the TNF doses given, nor was there any toxicity to the mice.

Adenocarcinoma↗