New targets for cancer therapy.
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Animals↗
Biomedical subjects
R C Coombes
Publications and source records attributed to R C Coombes.
The effect of endocrine therapy on fibroblast growth factor-like activity in nitrosomethylurea-induced rat mammary tumours.
Tumour regression following ovariectomy of rats bearing nitrosomethylurea-induced mammary tumours has been well characterised as a model for oestrogen receptor (ER)-positive breast cancer. We have shown that a similar regression response can be induced in these rats by the cytotoxic drug doxorubicin. Conditioned medium (CM) from serum-free explant cultures of the mammary tumours of ovariectomised rats showed a striking increase in its ability to transform NR6 cells compared to that of control or doxorubicin-treated rats (P = 0.001, t-test). Activity was also present in CM derived from rat uteri but not in ER-negative tissues such as skin and liver. Activity was further defined as fibroblast growth factor (FGF)-like by its strong affinity to heparin, partial neutralisation by antibodies to acidic FGF (aFGF) and partial co-elution with aFGF on salt elution from heparin. Both aFGF protein and mRNA were detected in tissue preparations of rat tumours and uterus.
Animals↗
A randomised prospective trial of surgical against medical tetracycline pleurodesis in the management of malignant pleural effusions secondary to breast cancer.
Malignant pleural effusion is a frequent complication of metastatic breast cancer leading to a significant degree of morbidity. Drainage of the effusion by thoracocentesis and pleurodesis with tetracycline as the sclerosing agent is an established means of symptomatic relief in these patients. To determine whether the efficacy of tetracycline pleurodesis is improved by surgical rather than medical drainage and instillation of sclerosant, 34 patients were prospectively randomised to a trial comparing the two treatment modalities, of whom 29 were evaluable for response. The total failure rate of primary pleurodesis was 13.4%, the rate of recurrence of effusion within the first month was 24%, and only 1 patient (3.4%) required repeat aspiration in that time period. There was no significant difference in the rate of recurrence or reaspiration of effusion between the two treatment groups. Although the overall survival time from treatment of effusion is significantly longer in the surgical treatment group than in the medical treatment group (P = 0.03), this is likely to be due to factors other than the method of treating the effusion. We conclude that surgical tetracycline pleurodesis has no advantage over medical tetracycline pleurodesis.
Adult↗
Prognostic significance of aromatase and estrone sulfatase enzymes in human breast cancer.
The aromatase and estrone sulfatase enzymes are important sources of local synthesis of biologically active estrogens in human breast cancer. Significant intratumoral aromatase activity was detected in 91/145 (63%) of tumors and estrone sulfatase was detected in 93/104 (89%) of tumors. There was no relationship between aromatase activity and tumor size, site, nodal status, menopausal status or estrogen receptor status. There was a significant correlation between the aromatase activity and histological grade, with an excess of aromatase-positive in the high grade tumors (P = 0.03). There was a marginally inverse correlation between the aromatase activity and time to relapse (P < 0.1), a significant correlation between aromatase activity and survival after relapse (P < 0.05) but not with overall survival (P > 0.1). Intratumoral estrone sulfatase activity was not significantly correlated to any putative prognostic factors, nor with time to relapse nor overall survival time.
Aromatase↗
Detection of breast cancer-associated estrone sulfatase in breast cancer biopsies and cell lines using polymerase chain reaction.
Steroid sulfatase (STS) is a single enzyme with a range of substrate specificities, including estrone sulfate. Using a 2.4 kb cDNA clone, expression of human STS was undetectable by Northern hybridization, but STS RNA was detected in human placenta, human breast cancer samples, and in breast carcinoma cell lines following reverse transcriptase-PCR amplification, using specific primers to yield a product of 472 bp. In preliminary studies, stimulation of MCF-7 cell lines with estradiol (10(-8) M) resulted in an increased level of amplifiable STS RNA, and this upregulation of STS RNA could be abolished by tamoxifen. The estrone sulfatase activity in mammary tumors derived from N-nitrosomethylurea (NMU) treated rats was significantly decreased in animals treated with tamoxifen compared to control animals, regardless of the response of the tumors to the antiestrogen (P < 0.05). Although tamoxifen does not inhibit the estrone sulfatase enzyme in vitro, it may modulate the expression of STS RNA and the enzyme activity in vivo.
Animals↗
Immunohistochemical localisation of pS2 protein in ductal carcinoma in situ and benign lesions of the breast.
The expression of pS2 was examined histochemically in paraffin sections taken from biopsy material from patients diagnosed with ductal carcinoma in situ (DCIS). Often intense immunoreactivity, to an anti-pS2 monoclonal antibody, was observed in comedo, solid, cribriform and micropapillary types of DCIS, with significant positivity found in 63-67% of cases. In 15 samples analysed, we found a good correlation between pS2 expression and presence of progesterone receptor positive cells, but not with estrogen receptor. There was only a limited degree of correspondence between the cells staining with these anti-sera. Some pS2 positive cells were also seen in normal acini in areas adjacent to cancer but much less frequently in sections of normal breast from reduction mammoplasty. Most normal areas were negative, as were cysts. In benign proliferative conditions (seen in sections with and without DCIS) such as adenosis, sclerosing adenosis, mild and florid ductal epithelial hyperplasia, significant pS2 positivity was seen in about 50% of cases. These results suggest that there is a progressive increase in pS2 from normal to benign to cancer cells and that this gene is expressed in both the invasive and pre-invasive forms of breast cancer.
Biopsy↗
The prognostic significance of transforming growth factors in human breast cancer.
Transforming growth factor alpha (TGF alpha) and Transforming growth factor beta-1 (TGF-beta 1) are growth regulatory for breast cancer cell lines in vitro and several studies have suggested that levels of the receptor for TGF alpha, the epidermal growth factor (EGFR) in tumour biopsies predict relapse and survival. We have examined the prognostic significance of TGF alpha, TGF-beta 1 and EGFR mRNA expression in a series of patients with primary breast cancer with a median follow up period of 60 months. In 167 patients the expression of TGF-beta 1 was inversely correlated with node status (P = 0.065) but not ER status, tumour size or menopausal status. Patients with high levels of TGF-beta 1 had a longer disease free interval with a significantly longer probability of survival at 80 months although the overall relapse free survival was not increased. EGFR mRNA expression was measured in 106 patients and was inversely correlated with ER status (P = 0.018). EGFR levels did not predict for early relapse or survival. TGF alpha mRNA levels were measured in 104 patients, no correlation was seen tumour size, node status, Er status, or clinical outcome.
Adenocarcinoma, Mucinous↗
Comparison of single-agent epirubicin and 5-fluorouracil/epirubicin/mitomycin in patients with advanced adenocarcinoma of the pancreas.
In a randomized trial we compared single-agent epirubicin with the FEM (5-fluorouracil/epirubicin/mitomycin) combination in patients with locally advanced and/or metastatic adenocarcinoma of the pancreas. Sixty patients previously untreated with radiotherapy or chemotherapy were randomly assigned to receive either 100 mg/m2 epirubicin or FEM in the following doses: 5-fluorouracil, 600 mg/m2 to a maximum of 1 g; epirubicin, 50 mg/m2; mitomycin, 6 mg/m2 to a maximum of 10 mg. Treatment was given every 28 days via intravenous bolus; because of its association with delayed myelotoxicity, mitomycin was given every other cycle. A total of 47 patients are evaluable for toxicity and survival, 22 who received FEM and 25 epirubicin. Preliminary results of this ongoing study show no difference in survival between the two arms. Toxicity has been easily managed. A similar number of patients in each arm had elevated serum bilirubin levels, but dose reductions of 50% allowed all these patients to continue treatment.
Adenocarcinoma↗
Design and rationale of a randomised comparison of cyclophosphamide, methotrexate and fluorouracil vs fluorouracil, epirubicin and cyclophosphamide in node-positive premenopausal women with operable breast cancer. A trial of the International Collaborative Cancer Group (ICCG).
In 1984, the International Collaborative Cancer Group (ICCG) started a randomised trial comparing adjuvant treatment with cyclophosphamide 100 mg/m2 orally on days 1 to 14, methotrexate 40 mg/m2 intravenously on days 1 and 8 plus fluorouracil 600 mg/m2 intravenously on days 1 and 8 every 4 weeks for 6 cycles (CMF) vs fluorouracil 600 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 600 mg/m2 (FEC), all given intravenously on day 1 for 8 cycles at 3-week intervals in premenopausal patients with node-positive breast cancer. However, a large French institution that joined the ICCG shortly after the trial was initiated utilised different schedules of both CMF and FEC. Because different dose intensities were also employed, particularly of FEC, both patient groups, the French and non-French, will be analysed separately. A total of 761 patients were randomised as of March 1992. Patients were well balanced for prognostic factors. The median follow-up is now 3.5 years. Preliminary data have previously been reported in abstract form. Final data will be presented pending further follow-up.
Administration, Oral↗
pS2 immunostaining of colorectal carcinoma.
This study was aimed at assessing the significance of pS2 immunostaining in colorectal adenocarcinoma and adjacent tissue. Paraffin sections of 63 surgically resected colorectal adenocarcinomas were stained with a pS2 specific monoclonal antibody using the avidin-biotin complex immunoperoxidase technique. Several tumor sections also included adjacent nonneoplastic mucosa. Six tubular adenomas and five hyperplasic polyps found in the resected bowels were also examined. Focal staining for pS2 was seen in 32 tumors (51%). In all but one case, less than 10% of the tumor cells were stained. pS2 staining was more common in right-sided than in left-sided tumors (p < 0.05), and was more prevalent in Dukes C than combined Dukes A and B tumors (p < 0.05). No significant relationship was found between pS2 positivity and the degree of tumor differentiation, patients' sex, or outcome of the disease as judged by the development of recurrence or metastasis. Strong pS2 positivity was seen in hyperplastic polyps and in nonneoplastic mucosa adjacent to many tumors. Tubular adenomas were either negative or showed focal superficial staining. It is concluded that pS2 immunostaining in colorectal adenocarcinoma does not seem to have prognostic significance, but may reflect developmental differences between the right and left side of the colon. The presence of pS2 staining in adjacent nonneoplastic mucosa and in hyperplastic polyps suggests that the epithelium in these areas is of a regenerative or reactive nature.
Adenocarcinoma↗
EB1089: a new vitamin D analogue that inhibits the growth of breast cancer cells in vivo and in vitro.
EB1089 is a novel vitamin D analogue which has been tested for its effects on breast cancer cell growth in vitro, using the established human breast cancer cell line MCF-7, and in vivo on the growth of established rat mammary tumours. Both EB1089 and 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) inhibited MCF-7 cell proliferation with the synthetic analogue being at least an order of magnitude more potent than the native hormone. In vivo anti-tumour effects were investigated using the N-methyl-nitrosourea-induced rat mammary tumour model. Oral treatment with EB1089 was tested at three doses. With the lower dose, significant inhibition of tumour growth was seen in the absence of a rise in serum calcium. The same dose of 1,25-(OH)2D3 had no effect on tumour growth but caused hypercalcaemia. With the higher dose of EB1089, striking tumour regression was seen although serum calcium rose. This report demonstrates that EB1089 possess enhanced anti-tumour activity coupled with reduced calcaemic effects relative to 1,25-(OH)2D3 and thus may have therapeutic potential as an anti-tumour agent.
Animals↗
Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women.
Aromatase inhibitors are a useful therapeutic option in the management of endocrine-dependent advanced breast cancer. A single-dose administration of exemestane (FCE 24304; 6-methylenandrosta-1,4-diene-3,17-dione), a new irreversible aromatase inhibitor, was investigated in 29 healthy postmenopausal female volunteers. The compound, given at p.o. doses of 0.5, 5, 12.5, 25, 50, 200, 400, and 800 mg (n = 3-4), was found to be a well tolerated, potent, long-lasting, and specific inhibitor of estrogen biosynthesis. The minimal dose which produced the maximum suppression of plasma estrogens was 25 mg, reducing plasma estrone, estradiol, and estrone sulfate to 35, 28, and 39% of basal values, respectively. This maximum suppression, observed at 3 days, persisted for at least 5 days after administration of a single dose. However, there was no interference on cortisol, aldosterone, 17-hydroxyprogesterone, or dehydroepiandrostenedione sulfate plasma levels. Peak plasma exemestane concentrations of 27, 221, 343, and 414 ng/ml were reached within 2 h after administration of 50, 200, 400, and 800 mg, respectively. Plasma concentrations declined rapidly and fell under the detection limit (10 ng/ml) at 4 (50 mg) or 24 h (200 and 400 mg). No clinically significant adverse events which could be attributed to the drug were reported. Apart from transient eosinophilia in 3 patients, all biochemical and hematological laboratory parameters were within 1.25-fold of the normal ranges.
Aged↗
Effects of synthetic vitamin D analogues on breast cancer cell proliferation in vivo and in vitro.
Calcipotriol (MC903) is a novel vitamin D analogue which effects cellular differentiation and proliferation in vitro and has reduced effects on calcium metabolism in vivo. In the present study its in vitro activity was evaluated using the MCF-7 breast cancer cell line, and its effects on calcium metabolism and mammary tumour growth were measured in vivo in adult female rats. Calcipotriol was compared to the natural metabolite of vitamin D3, 1 alpha,25-dihydroxycholecalciferol [1,25(OH)2D3] and its synthetic analogue 1 alpha hydroxycholecalciferol [1 alpha(OH)D3]. Both calcipotriol and 1,25(OH)2D3 produced significant inhibition of MCF-7 cell proliferation at a concentration of 5 x 10(-11) M. Intraperitoneal administration of calcipotriol to normal female rats showed that the analogue was 100-200 times less active than 1,25(OH)2D3 in raising serum calcium concentration and urinary calcium excretion. Anti-tumour activity of the vitamin D analogues was investigated in vivo using the nitrosomethylurea-induced rat mammary tumor model. Rats, maintained on a low calcium diet, were treated with 1 alpha(OH)D3 (0.25 and 1.25 micrograms/kg). Both doses produced a response rate of 25% but hypercalcaemia developed. Treatment with calcipotriol (50 micrograms/kg) of rats maintained on a normal laboratory diet caused inhibition of tumour progression (response rate 17%) without the development of severe hypercalcaemia. This study supports the concept that vitamin D derivatives may inhibit breast cancer cell proliferation in vivo.
Animals↗
Clinical and biological significance of HSP89 alpha in human breast cancer.
In order to isolate and characterize genes whose expression may be altered in breast malignancy, we screened a cDNA library with a polyclonal anti-serum against breast-cancer-metastasis membranes and isolated several immunopositive clones. One of these, AJ1, was analyzed in detail and found to be expressed at varying levels as a 3.3-kb mRNA in all of 143 breast cancers. High expression was associated with lymph-node involvement (p = 0.03). Comparison between high- and low-expressing groups showed a significant difference at 4 and 6 years for both overall (p = 0.004 and p = 0.002 respectively) and disease-free (p = 0.0001 and p = 0.04 respectively) survival, but not at 11 years. AJ1 was expressed at much lower levels in non-malignant biopsies as compared with malignant tissue (p = 0.001). Expression was observed in breast-cancer cell lines MCF-7, ZR-75-1, T47D, MDA-MB-231 and HBL 100. Partial sequence analysis of the 620 bp clone showed complete homology with human heat-shock protein 89 alpha. In addition to being heat-inducible in all the breast cell lines examined, AJ1 levels were increased by estradiol (blocked by cyclohexamide and tamoxifen), EGF, oxytocin and vasopressin in a time-dependent manner in MCF-7 cells and by estradiol, EGF, prolactin and hydrocortisone in T47D cells. In MDA-MB-231 cells, EGF caused down-regulation of AJ1 mRNA levels. The increasing evidence for the association of heat-shock proteins with steroid receptors suggests that AJ1 may play an important role in the control of estrogen-receptor transcriptional activity in breast cancers.
Blotting, Northern↗
Polymerase chain reaction-aided analysis of gene expression in frozen tissue sections.
A simple method for the detection and localization of mRNA in single frozen breast biopsy tissue sections is described. Several extraction procedures were compared. Resuspending sections, which could be left at 0 or -70 degrees C for up to 20 min in H2O containing RNAse inhibitor, optimally released RNA with minimal DNA contamination. Reverse transcription followed by polymerase chain reaction amplification using specific primers yielded products visible by ethidium bromide staining (abundant sequences) or after Southern blotting (low copy message). We found that it was possible, by microdissection, to separate stromal and tumor cells and demonstrated differential expression of several genes in the two populations. With 40 cycles of amplification, dissected stromal and tumor tissue both yielded products encoding glyceraldehyde 3'-phosphate dehydrogenase but only the tumor cells gave products with primers specific for either keratin 19, heat shock protein 89 alpha or the fig oncogene, which encodes one of the fibroblast growth factor receptors that we have recently found to be expressed in breast cancers. With refinement of the dissection technique this offers a very sensitive analytical tool for measuring and defining the cellular sites of synthesis of low-abundance message, requiring only single histological sections.
Base Sequence↗
An immunohistochemical survey of pS2 expression in human epithelial cancers.
The oestrogen-inducible pS2 protein isolated from human breast-cancer cells appears to have prognostic significance in breast-cancer patients. Using both monoclonal and polyclonal pS2 anti-sera, we have carried out an immunocytochemical survey of 9 epithelial cancers. Some degree of specific tumour staining was observed in 4 tissues, the extent varying greatly between specimens. Most (11/13) of the colorectal cancers showed immunoreactivity, as did 4/5 pancreatic carcinomas. In some of these cases, patchy staining was also observed in adjacent non-tumour cells. Two bronchio-alveolar carcinomas showed positivity, but 5 poorly differentiated adenocarcinomas of the lung did not. In the ovary, staining was observed in 3/3 mucinous cystadenocarcinomas but only in 1/8 of the serous type. No reactivity was seen in specimens of salivary gland, kidney, liver, prostate or uterus. This pilot study indicates that pS2 may be a useful marker of adenocarcinomas in human neoplasms apart from those in the breast, and suggests that more extensive surveys might be worthwhile.
Adenocarcinoma↗
Lactic acidosis. A presentation of metastatic breast cancer arising in pregnancy.
Lactic acidosis B is a rare metabolic complication of malignancy. It usually is associated with advanced and extensive metastatic disease. The authors report a case in which lactic acidosis was the presenting feature of a previously undiagnosed case of metastatic breast cancer in a pregnant woman and that resolved with successful antineoplastic treatment. The authors review the likely cause and management of the condition.
Acidosis, Lactic↗
A preliminary clinical study of gossypol in advanced human cancer.
A total of 34 patients with advanced cancer were given weekly or daily escalating doses of oral gossypol, a cottonseed-oil constituent showing evidence of antineoplastic activity in pre-clinical studies. No major adverse events occurred and there was no evidence of haematological or biochemical disturbance. As determined by dose escalation in 17 patients, the dose-limiting toxicity was emesis in 16 patients. There was no evidence of tumour regression in any of the 20 patients assessed for response. We conclude that gossypol is safe but unlikely to be clinically useful in patients with advanced cancer.
Adult↗