The chemopreventive properties of soy isoflavonoids in animal models of breast cancer

Genistein (5,7,4-trihydroxyisoflavone), one of two major isoflavonoids in soy, has anti-proliferative effects on mitogen-stimulated cell growth of human breast cancer cells in culture and is a candidate for use in the prevention of breast cancer. Soy protein preparations containing isoflavonoid conjugates have chemopreventive activity in carcinogen-induced rat models of breast cancer. Recent experiments in these models with purified genistein have revealed that the timing of the exposure of rats to this isoflavonoid is critical. Rats treated neonatally or prepuberally with genistein have a longer latency before the appearance of 7,12-dimethylbenz[a]anthracene-induced mammary tumors and a marked reduction in tumor number. The mechanism of genistein's preventive action is in part dependent on its estrogenic activity, which causes a more rapid differentiation of the cells of the mammary gland, analogous to the effects of an early pregnancy. Rats administered genistein after 35 days of age have smaller alterations in breast cancer risk, with a maximum reduction in mammary tumor number of 27%. In ovariectomized nude mice, dietary genistein increases cell proliferation of human breast cancer MCF-7 cell xenografts compared with a control diet. This estrogen-like effect of genistein is not observed in non-ovariectomized rats. Future studies on the anticancer potential of soy isoflavonoids should examine their interaction with other phytochemical components of soybeans and exploit newly developed animal models of breast cancer in which specific genes have been activated or inactivated.     

A point mutation in the human estrogen receptor gene is associated with the expression of an abnormal estrogen receptor mRNA containing a 69 novel nucleotide insertion

A novel ER-like mRNA containing a 69 nucleotideinsertion precisely between exon 5 and 6 sequenceswas previously identified in human breast cancer biopsysamples. Data are presented which suggest that the69 nucleotide sequence is normally present in intron5 of the human estrogen receptor gene. Theregion corresponding to and surrounding this 69 nucleotidesequence was cloned and the nucleotide sequence determined.Cloning and sequencing of the corresponding region ingenomic DNA isolated from a breast tumor expressingthe 69 nucleotide inserted ER mRNA, revealed anAG point mutation immediately 3 to the69 nucleotide sequence. This point mutation resulted inthe generation of a consensus splice donor site.A consensus splice acceptor site sequence is normallypresent immediately 5 to the 69 nucleotide sequence.These data are consistent with the 69 nucleotidesequence being recognized as an exon by thesplicing machinery, and resulting in processing of amature ER mRNA containing the 69 nucleotide insert.     

Consistency of patient- and doctor-assessed cosmetic outcome after conservative treatment of breast cancer

The cosmetic results of the breast (144 patients)were analysed after segmental resection and axillary dissectionwith or without postoperative radiotherapy for early low-riskbreast cancers. Cosmetic results were assessed over time(3, 9, 18, 36, 48 months respectively) bythe patient and by the physician. Patients ratedthe overall cosmetic result good or excellent in92% of cases after 3 months. The proportionof good or excellent cosmetic results decreased overtime and after four years 89% of patientsclassified themselves in this category, whereas the physicianassessed the outcome as good or excellent in91% of cases after 3 months and 75%after 4 years. The inter-observer consistency between physicianand patient in assessing the cosmetic outcome was=0.42 at the beginning and decreasedover time (=0.07 after 4 years).The intra-observer variation over time was =0.53 for the patient and =0.32for the physician.Inter-observer consistency between patient and physician was moderateimmediately following treatment but decreased over time. Thefeeling of satisfaction of the patient was relativelystable whereas the opinion of the physician becamesomewhat more critical over time. Therefore the intra-observerconsistency over time was somewhat better for thepatient than for the physician.     

Ten-year survival of patients with cancer of the digestive tract in Umbria, Italy

Survival statistics of 4135 incident cases of digestive system cancers in the Umbria region of Italy are reported. The original data are derived from an ad hoc survey carried out in the period 1978--1982. Observed and relative rates at 1, 5 and 10 years are presented separately by sex and age (< 60 and 60 years). In both sexes there are very short survival rates for liver, bile duct and pancreas cancers, whereas about 50% of colon and rectum cancer patients survived at five years. About 20% stomach cancer patients survived at the same time. In males the survival rate for oesophagus cancer is close to 10%. The rates at ten years confirm the trend. Comparisons between sexes show that there is no significant differences in age at first diagnosis. Survival values are higher in females only for rectum cancers. In both sexes, for stomach, colon and rectum sites younger patients had a significantly longer survival than older ones.     

Nitric oxide mediates inhibitory nerve effects in human esophagus and lower esophageal sphincter

The effect of inhibition of nitric oxide synthase on nonadrenergic, noncholinergic nerve-mediated responses in circular smooth muscle of the human esophageal body and lower esophageal sphincter (LES) was examinedin vitro. Tissues were obtained from 10 patients (eight esophageal resection for cancer, two transplant donors). Muscle strips from the LES developed significant spontaneous tension (11.6 ± 2.1 mN/mm²,N=6) and relaxed in response to electrical stimulation. The nitric oxide synthase inhibitor,N -nitro-l-arginine (NNA), at 10^–5 M, inhibited the relaxation, but had no significant effect on the spontaneous tension (13.0 ± 2.6 mN/mm²,P=0.07). Esophageal body strips developed little spontaneous tension, demonstrated an off contraction following the cessation of the electrical stimulus, and when contracted with 10^–5 M carbachol, relaxed during electrical stimulation. NNA (10^–5 M) inhibited the off contraction and the relaxation seen after carbachol and unmasked a prominent intrastimulus contraction. This intrastimulus contraction was enhanced by eserine and inhibited by atropine and tetrodotoxin. NNA showed similar potency in the esophageal body and LES and its effects were reversed byl-arginine, but notd-arginine. The results indicate that nitric oxide is an important mediator for nonadrenergic, noncholinergic nerve effects in the human esophagus and lower esophageal sphincter.This research was supported in part by an ICI Pharma/Medical Research Council of Canada Research Fellowship grant awarded to H.G. Preiksaitis and a Medical Research Council Program Grant PG8.     

Combinations of interferon with platinum complexes: synergistic and antagonistic effects on growth inhibition of MCF-7 and MDA-MB231 breast cancer cells

The growth-inhibitory effects of combining interferons (IFN) with platinum(II) complexes were tested with the aim of comparing these in cultures of estrogen-receptor(ER)-negative MDA-MB₂₃₁ and ER-positive MCF-7 breast cancer cell lines. Another aim was to test whether IFN as a biological response modifier could enhance the effect of the Pt complexes in vitro in an attempt to find an explanation for their more potent antitumor effects in in vivo models. Here it is shown that in both cell lines the combinations of different IFN with all three Pt complexes generally resulted in additive growth inhibition, as calculated by the product of the fraction of surviving cells obtained with each compound alone. Moreover, in MCF-7 cells natural IFN (nIFN) combined with aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) (meso-6-Pt) resulted in synergistic inhibition. This synergy could be attributed to the estrogenic property of meso-6-Pt, since the ligand and estradiol also enhanced the inhibitory effect of nIFN. In contrast, the combination of recombinant IFN and meso-6-Pt was antagonistic in MDA-MB₂₃₁ cells. These results show that, in spite of the similar responses of the ER-negative and ER-positive cells to each compound alone, these cells show unexpected differences in their sensitivity to combinations of IFN and the new Pt complex meso-6-Pt.Abbreviations ER estrogen receptor - IFN interferon(s) - nIFN natural interferon - rIFN recombinant interferon - meso-4-Pt aqua[meso-1,2-bis(2,6-difluoro-3-hydroxyphenyl)ethylenediamine]sulfatoplatinum(II) - meso-6-Pt aqua[meso-1,2-bis-(2,6-dichloro-4-hydroxyphenyl) ethylenediamine]sulfatoplatinum(II)     

Preservation of the pylorus during pancreaticoduodenectomy —Evolution and current indications

The Whipple procedure has been improved by preservation of afunctioning pylorus. A functioning pylorus is important because marginal ulceration is avoided and, compared to the standard Whipple procedure with hemigastrectomy, more patients can gain weight postoperatively. The most common indications for this procedure are severe complication of chronic pancreatitis and periampullary tumors. In patients with pancreatic adenocarcinoma, the pylorus-preserving variety results in equal or better survival rates than those of the standard Whipple procedure with hemigastrectomy. Surgery alone is not sufficient to improve survival rates in patients with adenocarcinoma of the pancreas. Improved imaging modalities are required to diagnose the disease earlier. The most likely combination of treatment to prolong survival time is a combination of resection for cure in a patient with an early diagnosis plus an aggressive adjuvant chemoradiotherapy protocol. This protocol is most likely to be completed if a patient has preserved endocrine, exocrine, and digestive ability. A radical (R1) pylorus-preserving Whipple procedure would have the following advantages to result in the best survival rates — the patients can gain weight and thereby withstand the chemoradiotherapy protocol while, at the same time, the weakest aspect of the radical resection is addressed, i.e., the retroperitoneal margin of the pancreatic head.     

Age-related differences in breast cancer treatment

Background: More than half of the cases of breast cancer treated in the United States occur in women over age 65. This study investigates age-related differences in breast cancer therapy. Methods: A retrospective review of all women with primary operable invasive breast cancer treated at the University of Michigan Breast Care Center over a 30-month period showed a total of 77 older patients aged 65 years (median, 71; oldest patient, 92) for whom full information was available regarding comorbidity, tumor stage and histology, and details of surgery, radiation, and chemohormonal therapy and complications. Fifty-one similar younger patients aged 55–64 years (median, 59) were identified for comparison. Patients were classified as either having received standard treatment or nonstandard treatment. Standard therapy was prospectively defined as follows: local/regional—lumpectomy and axillary lymph node dissection plus radiation therapy or modified radical mastectomy; systemic—chemotherapy and/or tamoxifen for stage II disease. A comorbidity score calculated for each patient assigned one point each for nursing home residence, nonambulatory status, recent surgery, and each medical problem requiring drug therapy. Results: When overall treatment (local/regional plus systemic) was assessed, proportionately fewer older patients (55 of 77 versus 47 of 51;p<0.01) received standard treatment. Fewer older than younger patients (62 of 77 versus 50 of 51;p<0.01) received surgical therapy that included an axillary dissection. A smaller proportion of older patients received radiation therapy following lumpectomy and axillary lymph node dissection (26 of 29 versus 19 of 19; N.S.). Overall, only 59 of 77 older patients versus 50 of 51 younger patients (p<0.001) received standard local/regional care. Similar proportions of younger and older patients (19 of 22 and 24 of 30, respectively) received standard systemic therapy for stage II breast cancer, but older patients were less likely to receive chemotherapy than younger patients (7% versus 50%;p<0.001). Treatment-related complications were not age-related but were more frequent in patients receiving standard treatment than in patients receiving nonstandard treatment (45 of 102 versus two of 26;p<0.001). Comorbidity score correlated with the use of nonstandard therapy but not with age. The scores for both older and younger patients receiving overall standard treatment were 0.8 versus 1.5 and 1.4, respectively, in patients receiving nonstandard treatment. Interestingly, explanations for decisions to deviate from standard treatment guidelines were often not identified. Comorbidity was explicitly noted in only one of four younger patients who received nonstandard treatment therapy. In 22 older patients who received nonstandard treatment, comorbidity was cited in eight cases, patient age was cited in six cases, and patient choice was cited in four cases. Follow-up (median, 34 months) did not show that disease-free or overall survival differences were related to age or to treatment (standard versus nonstandard). Conclusions: These data demonstrate age-related variations in breast cancer treatment in a multidisciplinary breast care unit. Lower complication rates and equivalent short-term outcomes in women who received nonstandard therapy suggest good clinical judgment may have played a role in these differences. Although age-related patient preferences and comorbidity are relevant, the age-related attitudes of caregivers must also be taken into account to fully explain these variations.Presented at the 46th Annual Cancer Symposium of the Society of Surgical Oncology, Los Angeles, March 18–21, 1993.     

The pharmacokinetics of high-dose epirubicin and of the cardioprotector ADR-529 given together with cyclophosphamide, 5-fluorouracil,and tamoxifen in metastatic breast-cancer patients

A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-m silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m²) together with different doses of epirubicin (E, 60–100 mg/m²), fixed-dose cyclophosphamide (C, 600 mg/m²), fixed-dose 5-fluorouracil (F, 600 mg/m²), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m². We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.     

Molecular genetic studies of early breast cancer evolution

Summary In the past few years there has been an explosion in the number of patients diagnosed with hyperplastic breast disease andin situ breast cancer. Based on epidemiological data, these morphologically defined lesions may be categorized as those with little malignant potential (e.g. typical hyperplasia or proliferative disease without atypia [PDWA]), those with significant malignant potential which may already be initiated (e.g. atypical ductal hyperplasia [ADH]), and early transformed lesions which are malignant but not yet invasive (e.g. ductal carcinomain situ [DCIS]). They may represent sequential evolutionary stages in the ontogeny of invasive breast cancer, with each morphologically defined stage resulting from accumulating genetic changes culminating in a transformed clonal lineage capable of invasion and metastasis. Using loss-of-heterozygosity (LOH) analysis, we are studying the genetic changes associated with these lesions in archival tissue samples. 50% (6/12) of the proliferative lesions (PDWA and ADH) and 80% of the DCIS shared their LOH patterns with more advanced lesions from the same breast, strongly supporting a precursor/product relationship between these lesions and the cancers they accompany.