Biomedical subjects
Publications and source records attributed to K D Bagshawe.
A patient developed severe neurological toxicity, with peripheral and cerebral components and hyponatraemia following one intrathecal injection of 80 mg cytosine arabinoside. The severity of his symptoms may reflect heavy prior neurotoxic chemotherapy.
The effect of etoposide containing drug combinations on reproductive performance was studied in women successfully treated for gestational trophoblastic disease between 1977 and 1984. Of the 74 women who wished to get pregnant 57 (77.0%) succeeded in having at least one live birth while five (6.8%) have ongoing pregnancies. Of eight (19.8%) women who have not become pregnant two (2.7%) had previous infertility problems antedating the development of gestational trophoblastic disease. The miscarriage rate was 124/1000. There was only one case of foetal death and one congenital abnormality (microcephaly possibly associated with cytomegalovirus infection) among 79 live births and stillbirths. This study indicates that etoposide (VP16-213) as is currently used in this unit for the treatment of gestational trophoblastic tumour is unlikely to have any long-term effect on fertility in most women.
We have treated eight patients with various tumours producing hCG or AFP with the high risk gestational choriocarcinoma regimen EMA/CO. Marker response was seen in two of three tumours producing AFP and in all of five tumours producing hCG. Three further patients were treated with EpPt/OMB, a regimen used in relapsed germ cell tumors. All responded biochemically. All complete biochemical responses were accompanied by anatomical response. These responses may reflect particular sensitivity in the marker producing tumours and marker measurements would identify this subgroup. These findings do not preclude the possibility that these cytotoxic regimens may have activity against a wide range of solid tumours.
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Carboxypeptidase G2, a zinc metalloenzyme isolated from Pseudomonas sp. strain RS-16, which catalyses the hydrolytic cleavage of reduced and non-reduced folates to pteroates and L-glutamate, has been linked to a monoclonal antibody (W14A) raised to human chorionic gonadotrophin. The coupling efficiency and retention of antibody and enzymatic activities are compared for three separate methods of preparing 1:1 conjugates. Preliminary in vitro studies on the cytotoxicity of the free enzyme and the conjugated enzyme towards JAR choriocarcinoma cells are reported. Despite the limitations of the in vitro model, it could be demonstrated that a significant proportion of 10(6) choriocarcinoma cells lost viability when exposed to either free or conjugated enzyme for 72 hours at concentrations of carboxypeptidase G2 of 1-3 units ml-1 of medium.
Between 1977 and 1985, 149 male patients with anaplastic germ cell tumours (AGCT) completed chemotherapy with POMB/ACE (platinum, vincristine (oncovine), methotrexate, bleomycin, actinomycin D, cyclophosphamide and etoposide). By increasing the number of courses of POMB in 1979, we have been able to compensate for adverse prognostic factors. Since then each patient has received at least three courses of POMB and 118 patients have completed therapy. The overall survival rate since 1979 is 89% and for the 100 patients who had not received prior radiotherapy it is 92%. We established that an initial serum concentration of human chorionic gonadotrophin (HCG greater than 50,000 iu/l) and/or alphafetoprotein (AFP greater than 500 ku/l) indicated a poor prognosis. Between 1977 and 1979 the survival rate in 12 patients in this category was only 45%. After increasing the number of courses of POMB, the survival rate rose to 89% in 31 patients. However, patients who had received prior radiotherapy and who presented with high tumour markers (HCG greater than 50,000 iu/l and/or AFP greater than 500 ku/l) continue to have a poor survival rate (20% in five patients). With this chemotherapy, 14 of 16 patients (88%) presenting with liver metastases and 6 of 7 patients (86%) presenting with brain metastases are in complete remission. Neither the stage at presentation nor the volume of metastatic disease was a major adverse prognostic variable. We believe that POMB/ACE chemotherapy, followed by surgery in selected cases, is currently the best treatment for patients with AGCT.
Identification of various prognostic factors at the start of chemotherapy allows patients with gestational trophoblastic tumours to be categorized into low-, medium- and high-risk groups so that they can be given the minimum treatment necessary to eliminate their disease. Most patients in the low-risk category can be treated with minimal toxicity using a methotrexate/folinic acid regimen and these patients are not considered in this report. Before 1979 patients in the medium-risk category were treated with a sequence of drugs which included, hydroxyurea, methotrexate, 6-mercaptopurine, actinomycin D, vincristine and cyclophosphamide. Since 1979 etoposide has been substituted for vincristine and cyclophosphamide. The 76 patients treated between 1979 and 1983 are all alive and in remission 1.1.85. Three patients (4%) relapsed and required retreatment and all are in remission. Fifty-six patients in the high-risk group, most at risk of developing drug resistance, were treated with a regimen incorporating etoposide with methotrexate, actinomycin D (EMA) and vincristine and cyclophosphamide (CO). EMA and CO were given on alternate weeks, resulting in an overall survival rate of 84%. Patients who had received prior chemotherapy had a survival rate of 74% and a relapse rate of 19% compared with 93% survival and 3% relapse rate in those who had not received prior chemotherapy. Toxicity with the EMA/CO regimen was significantly less than with an earlier regimen (CHAMOCA) used in the high-risk group.
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A new monoclonal anti-CEA antibody (1H12) has been raised which has localising characteristics in a human colon tumour xenograft which could make it suitable for human immuno-radiotherapy. The amount of 1H12 localising in tumour reached about 5% of the injected dose by 7 hours. This rate appeared to be related to the concentration of 1H12 in the blood pool since non-excretory normal organs such as colon and stomach accumulated similar amounts up to 4 hours. Whereas 1H12 was lost from normal organs after 4 hours, the amount in the tumour continued to increase slightly reaching a maximum concentration of 6.5% of the injected dose by day 9. Prolonged retention of 1H12 in tumour enabled increasing tumour: normal tissue ratios to be attained during the residence time of the antibody thus providing scope for maximising the dose of radiation delivered to tumour cells. Preliminary dose escalation showed that up to 500 micrograms of 1H12 could be administered with increasing concentrations of antibody localising in tumour. Saturation of the tumour site was evident in only one mouse where 1.09 micrograms of 1H12 actually localised--equivalent to 60 micrograms per gram of tumour.
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A Cornish-Bowden direct linear plot was used to assess the level of specific monoclonal antibody in a protein A preparation from mouse ascitic fluid. With this method, experimental observations are plotted directly as lines in parameter space and estimates of kinetic parameters are read directly from the plot without need for further calculation. This method is particularly well suited for the analysis of systems, such as the one outlined here, where conventional kinetic analysis is not possible because the preparation contains both specific and non-specific antibody. Results obtained with the direct linear plot showed that estimates of the level of specific immunoglobulin present in a given protein A preparation are consistent, not only within individual experiments, but also throughout a series of experiments using more than one labelled antibody preparation.
Serum levels of etoposide obtained 5 min after administration of 100 mg/m2 were between 11 and 30 micrograms/ml. By 24 h after drug administration, serum levels had fallen to between 0.19 and 1.11 micrograms/ml. Interpatient variation of etoposide serum concentrations obtained 5 min after drug administration was low, whereas interpatient variation 24 h later was noticeably higher. A significant correlation was observed (r = -0.698) between the WBC nadir and the mean etoposide serum concentrations, measured 24 h after drug administration, in patients receiving etoposide in combination with cyclophosphamide and actinomycin D. However, a relationship was not observed in those patients receiving etoposide alone. There was no observed difference in the efficacy or toxicity of 500 mg/m2 etoposide when the dose was administered either as 100 mg/m2 on each of 5 consecutive days or as 250 mg/m2 on days 1 and 3. There was no significant difference between AUC values calculated from etoposide concentration versus time profiles in patients receiving the drug on days 1 and 3 and those values obtained with the 5-day schedule. Patients resistant to a conventional dose of etoposide were given a higher dose of 1 g/m2/24 h, but this schedule did not cause an increase in efficacy despite an increase in serum levels of the drug. CSF levels in two of these patients receiving high-dose etoposide were 1.28% and 2.09% of the serum concentrations.
The dynamics of distribution of radiolabelled F(ab')2 fragments of a monoclonal anti-CEA antibody have been studied in the nude mouse bearing a CEA-producing human colon carcinoma. Our results showed that the fragment was rapidly cleared from all normal organs reaching about 1% of that injected by 24 hr. Specific tumour localization occurred as early as 2 hr after injection and was complete by 4 hr. The amount of fragment localized in tumour was 4% of the injected dose, equivalent to that obtained with the intact antibody. Greatly improved tumour:normal tissue ratios were obtained with the fragment compared to intact IgG. However, the residence time of the fragment was much shorter (24 hr) than that of intact antibody (more than 3 days). Tumour localization indices suggested that fragments were superior to intact IgG at locating tumour specifically. The specificity indices based on lung, spleen and liver were much higher than those for intact antibody, reflecting the lack of Fc-receptor binding of fragments and their reduced excretion by these organs. The 'fragment index' enabled tumour:normal tissue ratios for the fragment and intact IgG to be compared. Together with the distribution study at different time points, this simplifies the task of defining a 'time window' in which tumour imaging and therapy might be optimal.
Although virtually 100% of women who develop gestational trophoblastic tumors enter a long-term complete remission, there are many aspects of trophoblastic disease that arouse interest. Epidemiological studies have shown a large geographical variation in the percentage of conceptions that result in a hydatidiform mole and have stimulated studies on the immunological differences of the low and high risk populations. Chromosomal analysis is now complementing the pathological differentiation between complete and partial moles. There is still debate as to which factors are positively associated with the progression of a hydatidiform mole through invasive mole to choriocarcinoma. There are also considerable differences in the proportion of molar patients receiving chemotherapy in different centers. In addition to these topics, this article will review several recently introduced treatment regimens which show improved results with reduced toxicity.
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