The in vitro effects and cross-resistance patterns of some novel anthracyclinesTwentyman, P R; Fox, N E; Wright, K A; Workman, P; Broadhurst, M J; Martin, J A; Bleehen, N M
doi: 10.1038/bjc.1986.100pmid: 3459509
A range of new anthracyclines, structurally related to adriamycin (ADM), has been synthesised and studied in vitro. Three compounds described in this paper (Ro 31-1215; Ro 31-1741; Ro 31-2035) are all 4-demethoxyanthracyclines. In the mouse mammary tumour cell line, EMT6/Ca/VJAC, using a 1 h drug exposure followed by colony formation as the response endpoint, we found Ro 31-1215 and Ro 31-1741 to be 2-3 x and 4-7 x more potent then ADM, whilst Ro 31-2035 was 3-4 x less potent. For continuous drug exposure and suppression of population growth as the endpoint, the potency of Ro 31-1741 was similar to that of ADM, whereas that of Ro 31-1215 was 1.5-2 x higher and that of Ro 31-2035 was 10-20 x lower. The potency ratios for continuous drug exposure of a human small cell lung cancer line were similar to those for continuous exposure of EMT6. Variants of the two cell lines selected for resistance to ADM were also studied. These variants also showed considerable resistance to Ro 31-1741 and Ro 31-2035 but much less resistance to Ro 31-1215 (a 9-methyl derivative). A variant of EMT6 made resistant to Ro 31-1215 by continuous growth in this drug was more resistant to ADM than it was to Ro 31-1215. Human cells resistant to ADM contained 6 x less ADM after 24 h exposure than did the parent line, whereas the ratio of drug content for Ro 31-1215 was only 2.
Low central nervous system penetration of N2,N4,N6,-trihydroxymethyl-N2,N4,N6,-trimethylmelamine (Trimelamol): A cytotoxic s-triazine with reduced neurotoxicityJudson, I R; Rutty, C J; Abel, G; Graham, M A
doi: 10.1038/bjc.1986.102pmid: 3087399
Trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine) is an analogue of pentamethylmelamine (PMM). In early clinical trials PMM failed to show significant anti-tumour activity in man which was attributed to poor metabolic activation. Trimelamol does not require activation and is therefore expected to be more active in man. PMM caused dose-limiting emesis and sedation whereas Trimelamol is much less neurotoxic in rodents. The relative penetration of PMM and Trimelamol into mouse brain has therefore been examined. Mice receiving PMM at 90 mg kg-1 i.p. were found to have high concentrations of the drug in the CNS compared to plasma (mean brain/plasma ratio 1.04) whereas animals receiving Trimelamol had consistently low CNS concentrations (mean brain/plasma ratio 0.08). This difference did not correlate with plasma protein binding which is greater for PMM (68.2%) than for Trimelamol (17.5%). However, it does appear to be related to lipophilicity. In Phase I clinical trial Trimelamol has proved much less emetic than PMM and causes no acute sedation. It is likely that this reduction in toxicity may be explained by the relatively poor ability of Trimelamol to enter the CNS.
Effects of verapamil and alcohol on blood flow, melphalan uptake and cytotoxicity, in murine fibrosarcomas and human melanoma xenograftsRobinson, B A; Clutterbuck, R D; Millar, J L; McElwain, T J
doi: 10.1038/bjc.1986.103pmid: 3718818
Verapamil had previously been shown to increase cellular melphalan uptake and cytotoxicity in fibrosarcomas, and increased the area under the blood concentration versus time curve (AUC) for melphalan in CBA mice. Verapamil (10 mg kg-1 i.p.) had no effect on the fractional distribution of cardiac output (FDCO), measured with 86Rb-rubidium chloride, to subcutaneous fibrosarcomas. 14C-Melphalan uptake by FS13 fibrosarcomas was increased 60 min after verapamil (10 mg kg-1 i.p.), but not after lower doses which did not affect the AUC. Flunarizine (5 mg kg-1 i.p.) also had no effect on FDCO to FS13 fibrosarcomas, and tended to increase 14C-melphalan content of blood and the fibrosarcomas and to promote growth delay by melphalan. Alcohol increased FDCO to FS13 fibrosarcomas, maximally at a 1:20 dilution in saline, but had no effect on 14C-melphalan uptake or growth delay. Thus, melphalan cytotoxicity correlated with tumour melphalan uptake, and both followed changes in the AUC for melphalan but not changes in FDCO. In these murine fibrosarcomas melphalan uptake and cytotoxicity were not limited by blood flow. In subcutaneous human melanoma HX46 xenografts, verapamil had no effect on the FDCO, nor on 14C-melphalan uptake, and did not affect blood 14C-melphalan levels, suggesting absence of effects on the AUC and on cellular uptake. Alcohol did not increase the FDCO to HX46 xenografts, providing evidence for a different vascular supply.
Controlled targeting of different subcellular sites by porphyrins in tumour-bearing miceJori, G; Reddi, E; Cozzani, I; Tomio, L
doi: 10.1038/bjc.1986.104pmid: 3718819
Unilamellar liposomes of dipalmitoyl-phosphatidylcholine can incorporate various porphyrins in either the phospholipid bilayer or the internal aqueous compartment depending on the water-/lipo-solubility of the drug. Intraperitoneal injection of the liposome-bound porphyrins to mice bearing a MS-2 fibrosarcoma results in remarkably more efficient tumour targeting than that obtained by administration of the same porphyrins dissolved in homogeneous aqueous solution. Moreover, also water-insoluble porphyrins can be transported to the tumour via liposomes. Fractionation of liver and neoplastic cells indicates that the subcellular distribution of liposome-delivered porphyrins is also dependent on their solubility properties: thus, relatively polar porphyrins, such as tetra(4-sulfonatophenyl)porphine and uroporphyrin, are mainly recovered from the soluble fraction, whereas hydrophobic porphyrins, such as haematoporphyrin or porphyrin esters, preferentially partition in the cytoplasmic membrane. As a consequence, different subcellular sites can be targeted by porphyrins and possibly photodamaged through a suitable choice of the drug-carrier system.
The role of radiotherapy after chemotherapy in the management of persistent para-aortic nodal disease in non-seminomatous germ cell tumoursRead, G; Johnson, R J; Wilkinson, P M
doi: 10.1038/bjc.1986.105pmid: 3718820
In the years 1979-1982, 83 patients with malignant teratoma of the testis who had retroperitoneal adenopathy at presentation or after a period of surveillance were treated. Complete radiological resolution of disease was obtained in 34 patients and a residual mass remained in 26, the remainder having progression of the para-aortic or other metastatic disease. There was no para-aortic relapse in 47 patients receiving radiotherapy post-chemotherapy whereas 2/11 who did not receive radiotherapy or an immediate retroperitoneal node dissection relapsed. Morbidity from radiotherapy was minimal apart from subcutaneous fibrosis in the irradiated area of 6 patients. It is concluded that radiotherapy is effective in sterilising minimal residual tumour post-chemotherapy and may be considered as an alternative to surgery.
γ -Glutamyltranspeptidase activity in human breast lesions: An unfavourable prognostic signBard, S; Noël, P; Chauvin, F; Quash, G
doi: 10.1038/bjc.1986.107pmid: 2872909
The activity of gamma-glutamyltranspeptidase (gamma GT) (EC 2.3.2.2) was examined by histoenzymatic labelling on frozen sections derived from normal breast tissue, benign lesions and carcinomas. In biopsies from normal tissue and benign lesions, labelling was very intense in lumina and in the apical pole of the cells lining the lumina whilst in the cytoplasm it was slightly positive. In 34 out of 70 carcinomas, gamma GT activity was either undetectable or slightly positive while in the remaining 36 there was intense activity. Statistical examination of the results revealed no obvious correlation of gamma GT activity with histological grade of the tumour, progesterone receptor content or classification of patients by pre- or postmenopausal status. A good correlation between gamma GT activity and the following unfavourable prognostic signs: lymph node metastases and absence of oestradiol receptors. Patients with gamma GT-negative tumours may have a more favourable prognosis than those with gamma GT-positive tumours.
Cancer of the cervix uteri and vitamin AHarris, R W; Forman, D; Doll, R; Vessey, M P; Wald, N J
doi: 10.1038/bjc.1986.109pmid: 3718822
The concentrations of retinol and beta carotene were measured in serum samples taken from 113 women with cervical cancer, 32 with invasive and 81 with pre-invasive disease, and compared with those from 226 age-matched control women. There was little difference in serum retinol levels between women with cancer of the cervix, at any stage, and the control women, after adjusting for potential confounding factors. Serum beta carotene concentrations were likewise similar in women with invasive disease and the controls. However mean beta carotene levels were significantly reduced in women with pre-invasive disease compared to the controls (221.3 cf. 291.6 micrograms l-1, P less than 0.05). This reduction was more evident amongst women with a diagnosis of carcinoma-in-situ (mean 213.1 micrograms l-1 than amongst those with severe dysplasia (mean 228.7 micrograms l-1. There is a negative trend between beta carotene and risk of pre-invasive disease which is of borderline significance. These data have also been used to investigate the effects of smoking and oral contraceptive usage on the serum levels of retinol and beta carotene. Both habits tend to increase retinol and decrease beta carotene concentrations.