Showing papers in "Endocrine-related Cancer in 2001"

The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification.

Abstract: Homeostasis of multicellular organisms is critically dependent on the correct interpretation of the plethora of signals which cells are exposed to during their lifespan. Various soluble factors regulate the activation state of cellular receptors which are coupled to a complex signal transduction network that ultimately generates signals defining the required biological response. The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases represents both key regulators of normal cellular development as well as critical players in a variety of pathophysiological phenomena. The aim of this review is to give a broad overview of signal transduction networks that are controlled by the EGFR superfamily of receptors in health and disease and its application for target-selective therapeutic intervention. Since the EGFR and HER2 were recently identified as critical players in the transduction of signals by a variety of cell surface receptors, such as G-protein-coupled receptors and integrins, our special focus is the mechanisms and significance of the interconnectivity between heterologous signalling systems.

mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer.

Abstract: The mammalian target of rapamycin (mTOR) is a central regulator of G1 cell cycle protein synthesis that precedes commitment to normal cellular replication. We have studied the effect of cell cycle inhibitor-779 (CCI-779), a rapamycin ester that inhibits mTOR function, on the proliferation of a panel of breast cancer cell lines. Six of eight lines studied were sensitive (IC(50) 1.0 microM) to CCI-779. Sensitive lines were estrogen dependent (MCF-7, BT-474, T-47D), or lacked expression of the tumor suppressor PTEN (MDA-MB-468, BT-549), and/or overexpressed the Her-2/neu oncogene (SKBR-3, BT-474). Resistant lines (MDA-MB-435, MDA-MB-231) shared none of these properties. CCI-779 (50 nM) inhibited mTOR function in both a sensitive and a resistant line. In nu/nu mouse xenografts, CCI-779 inhibited growth of MDA-MB-468 (sensitive) but not MDA-MB-435 resistant tumors. Treatment of sensitive lines with CCI-779 resulted in a decrease in D-type cyclin and c-myc levels and an increase in p27(kip-1) levels. There was good correlation between activation of the Akt pathway and sensitivity to CCI-779. Amplification of mTOR-regulated p70S6 kinase, which is downstream of Akt, may also have conferred CCI-779 sensitivity to MCF-7 cells. Taken together, the data suggest that mTOR may be a good target for breast cancer therapy, especially in tumors with Akt activation resulting from either growth factor dependency or loss of PTEN function.

Discovery of a novel Raf kinase inhibitor

Abstract: We discuss the biology of Ras signal transduction and the epidemiology of ras mutations in association with disease as a background for the development of a Raf kinase inhibitor, BAY 43-9006. Knowledge of Ras effector pathways has permitted genetic validation of numerous targets involved in the Ras signaling cascade. A key Ras effector pathway involves the kinase cascade RAF/MEK/ERK (MEK: MAP/ERK kinase; ERK: extracellular signal related kinase). Indeed, we present studies of cell lines stably expressing mutant MEK constructs, which point to Raf kinase as a target for therapeutics with selective anti-tumor activity. Finally, a small molecule drug discovery program based on inhibition of Raf kinase activity is outlined and the initial pre-clinical development process of the Raf kinase inhibitor BAY 43-9006 is discussed.

Histological and biological evolution of human premalignant breast disease.

Abstract: Most human invasive breast cancers (IBCs) appear to develop over long periods of time from certain pre-existing benign lesions. Of the many types of benign lesions in the human breast, only a few appear to have significant premalignant potential. The best characterized of these include atypical hyperplasias and in situ carcinomas and both categories are probably well on along the evolutionary pathway to IBC. Very little is known about earlier premalignant alterations. All types of premalignant breast lesions are relatively common but only a small proportion appear to progress to IBC. They are currently defined by their histological features and their prognosis is imprecisely estimated from indirect epidemiological evidence. Although lesions within specific categories look alike, they must possess underlying biological differences causing some to remain stable and others to progress. Recent studies suggest that they evolve by highly diverse genetic mechanisms and research into these altered pathways may identify specific early defects that can be targeted to prevent premalignant lesions from developing or becoming cancerous. It is far more rational to think that breast cancer can be prevented than cured once it has developed fully. This review discusses histological models of human premalignant breast disease that provide the framework for scientific investigations into the biological alterations behind them and examples of specific biological alterations that appear to be particularly important.

Receptor tyrosine kinase signalling as a target for cancer intervention strategies.

Abstract: In multicellular organisms, communication between individual cells is essential for the regulation and coordination of complex cellular processes such as growth, differentiation, migration and apoptosis. The plethora of signal transduction networks mediating these biological processes is regulated in part by polypeptide growth factors that can generate signals by activating cell surface receptors either in paracrine or autocrine manner. The primary mediators of such physiological cell responses are receptor tyrosine kinases (RTKs) that couple ligand binding to downstream signalling cascades and gene transcription. Investigations over the past 18 years have revealed that RTKs are not only key regulators of normal cellular processes but are also critically involved in the development and progression of human cancers. Therefore, signalling pathways controlled by tyrosine kinases offer unique opportunities for pharmaco logical intervention. The aim of this review is to give a broad overview of RTK signalling involved in tumorigenesis and the possibility of target-selective intervention for anti-cancer therapy.

The epidermal growth factor receptor as a target for cancer therapy.

Abstract: Epidermal growth factor (EGF) receptors are expressed at high levels in about one third of epithelial cancers, and autocrine activation of EGF receptors appears to be critical for the growth of many tumors. We hypothesized that blockade of the binding sites for EGF and transforming growth factor-alpha on EGF receptors with an antireceptor monoclonal antibody (mAb) might be an effective anti-cancer therapy. We produced murine mAb 225 against EGF receptors and demonstrated blockade of receptor function, as well as inhibition of cell growth in cultures and in nude mouse xenografts. mAb C225 is the human:murine chimeric version of mAb 225. Cell cycle inhibition occurred in G(1) phase, and was due to upregulation of p27(Kip1), resulting in inhibition of cyclin E/cyclin dependent kinase-2 activity and hypophosphorylation of Rb. In addition, the amount and/or activities of a number of proapoptotic molecules were enhanced. The antitumor activity in vivo against xenografts was at least partly attributable to reduced vascularization, resulting from decreased vascular endothelial growth factor and basic fibroblast growth factor production by the tumor cells. Metastasis of xenografts was curtailed with mAB C225 treatment, accompanied by a decrease in tumor production of MMP-9. Further studies showed that mAbs 225 and C225 enhanced the cytotoxicity of chemotherapy against xenografts of a variety of human cancer cell lines. Well established xenografts resistant to either mAb or drug treatment alone were eradicated by the combination therapy. Drugs for which this has been demonstrated include doxorubicin, paclitaxel, cisplatin, and topotecan. Antibody treatment also potentiated the responsiveness of human tumor xenografts to radiation therapy. These findings led to clinical trials of human:murine chimeric mAb C225 in combination with chemotherapy or radiotherapy. Results from phase I and II trials involving more than 500 patients are quite promising, in particular in advanced head and neck cancer treated with C225 plus cisplatin or radiation, in advanced colon cancer treated with C225 plus CPT-11, and in advanced pancreatic cancer treated with C225 plus gemcitabine. Phase III trials are now underway.

EGF mutant receptor vIII as a molecular target in cancer therapy.

Abstract: In the year 2000, an estimated 1220 100 new cases of invasive cancer will be diagnosed in the United States, and about 552 200 people are expected to die of it (Greenlee et al. 2000). Treatment of cancer has conventionally consisted of surgery, radiation and chemotherapy. Despite improved cancer therapy involving early detection, the surgical removal of solid tumor masses, and the use of radiotherapy, cytotoxic agents, or both, truly effective therapeutic approaches are still lacking and thus urgently needed. Extensive analyses have defined tumor-associated and, less frequently, tumor-specific, surface antigens displayed on the malignant cell surface. Targeting cells selectively through these surface antigens by molecular probes is inherently different from surgery, radiation, and chemotherapy and has been considered as a favored modality for cancer therapy. A considerable effort has been made over the past decade to develop new immunotherapeutic strategies against cancer; recently, such strategies have shown promise (Waksal 1999, Yang et al. 1999, Kreitman et al. 2000). Targeted therapy can be accomplished by using tumor-specific monoclonal antibodies (Mabs) alone or Mabs armed with radionuclides, prodrugs, or toxins, which selectively kill tumor cells while not destroying normal cells. Many growth factors and their receptors play important roles in modulating cell division, proliferation and differentiation, and the possibility of disrupting these processes has led to the development of novel therapeutic agents for cancer treatment. Therefore, growth factor receptors are attractive candidates for targeted therapy, as they are often overexpressed on the surface of cancer cells. Among these, the type I epidermal growth factor (EGF)-related family of tyrosine kinase growth factor receptors are expressed in a broad spectrum of tumor types, which classifies them as one of the most frequently implicated cell-surface markers for human cancers. This family consists of four members: EGF receptor (EGFR), ErbB-2, ErbB-3 and ErbB-4 (Gullick 1998). EGFR was the first cell-surface glycoprotein identified to be amplified and rearranged in glioblastoma multiforme (GBM) and to act

Cyclooxygenase-2: a target for the prevention and treatment of breast cancer.

Abstract: Cyclooxygenase-2 (COX-2), an inducible prostaglandin synthase, is normally expressed in parts of the kidney and brain. Aberrant COX-2 expression was first reported in colorectal carcinomas and adenomas, and has now been detected in various human cancers, including those of the breast. Strikingly, COX-2 overexpression in murine mammary gland is sufficient to cause tumour formation. To date, the role of COX-2 in tumorigenesis has been most intensively studied in the colon. Thus, the relationship between COX-2 and neoplasia can best be illustrated with reference to intestinal tumorigenesis. Here we consider the potential utility of selective COX-2 inhibitors for the prevention and treatment of breast cancer. Data for cancers of the colon and breast are compared where possible. In addition, the mechanisms by which COX-2 is upregulated in cancers and contributes to tumorigenesis are discussed. Importantly, several recent studies of mammary tumorigenesis in animal models have found selective COX-2 inhibitors to be effective in the prevention and treatment of breast cancer. Clinical trials will be needed to determine whether COX-2 inhibition represents a useful approach to preventing or treating human breast cancer. Endocrine-Related Cancer (2001) 8 97–114

The IGF system and breast cancer.

Abstract: The IGF system components have been implicated in breast cancer progression. IGF-I and IGF-II are mitogenic and anti-apoptotic peptides that influence the proliferation of various cell types including normal and transformed breast epithelial cells. The IGF system is a key growth regulatory pathway in breast cancer. As various components of the IGF system have been directly or indirectly implicated in breast cancer, it is essential to gain a better understanding of these in order to develop more specific therapeutic strategies for treating breast cancer.

DNA methylation in breast cancer

Abstract: Like all cancers, breast cancer is considered to result in part from the accumulation of multiple genetic alterations leading to oncogene overexpression and tumor suppressor loss. More recently, the role of epigenetic change as a distinct and crucial mechanism to silence a variety of methylated tissue-specific and imprinted genes has emerged in many cancer types. This review will briefly discuss basic aspects of DNA methylation, recent advances in DNA methyltransferases, the role of altered chromatin organization and the concept of gene transcriptional regulation built on methylated CpGs. In particular, we discuss epigenetic regulation of certain critical tumor suppressor and growth regulatory genes implicated in breast cancer, and its relevance to breast cancer diagnosis, prognosis, progression and therapy.

Pituitary tumors: pathophysiology, clinical manifestations and management.

Abstract: Pituitary tumors are frequently encountered intracranial neoplasms. They present with a variety of clinical manifestations that include symptoms and signs of excessive hormone secretion by the tumor, signs of hormone deficits by the normal pituitary gland and others related to expansion of the tumor mass and the resulting compression of surrounding structures such as the optic chiasm and cranial nerves. Advances in molecular biology, immunocytochemical staining and imaging, and the introduction of new treatment options have improved our understanding of the natural history of these adenomas and their management. Available treatments include surgical, medical and radiation therapy. Although the primary treatment for each tumor type may vary, it is important to consider all available options and select the most applicable for that patient. The interaction of all members of management team, including the primary care provider, the endocrinologist and the neurosurgeon in selecting the treatment course can only improve therapeutic outcome. Regardless of the initial choice of treatment,follow-up of all patients should be maintained indefinitely. The managing physician should be familiar with the natural history and long-term complications of pituitary adenomas, and with the side effects of treatments given over the years.

Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer.

Abstract: Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer. Hormonal therapy leads to improved survival in oestrogen receptor (ER) positive early breast cancer and long-term responses in advanced disease. However, resistance to such therapy is a serious clinical problem. This article considers the data for and against there being a significant role for the oncogene HER-2 in such resistance. Transfection of HER-2 into MCF-7 cells leads to resistance to tamoxifen but data differ in relation to the oestrogen dependence of such cells. A number of retrospective studies have been conducted of HER-2 status in adjuvant trials of tamoxifen. Most of these also suggest a negative role but individually the studies do not have the statistical power to be conclusive. Recent studies in the neoadjuvant context have shown a significant antiproliferative effect of endocrine therapy in HER-2 positive/ER positive tumours but this is much less than in HER-2 negative/ER positive tumours. It is concluded that incomplete hormonal resistance results, from co-expression of HER-2 and ER and that this may differ between different hormonal agents.

Modulation of epidermal growth factor receptor in endocrine-resistant, oestrogen receptor-positive breast cancer.

Abstract: There is an increasing body of evidence demonstrating that growth factor networks are highly interactive with oestrogen receptor (ER) signalling in the control of breast cancer growth. As such, tumour responses to anti- hormones are likely to be a composite of the ER and growth factor inhibitory activity of these agents. The current article examines the modulation of growth factor networks during endocrine response, and presents in vitro and clinical evidence that epidermal growth factor receptor signalling, maintained in either an ER-dependent or -independent manner, is critical to anti- hormonal-resistant breast cancer cell growth. The considerable potential of the epidermal growth factor receptor-selective tyrosine kinase inhibitor, ZD 1839 (Iressa; AstraZeneca) to efficiently treat, and perhaps even prevent, endocrine-resistant breast cancer is highlighted.

The ErbB receptor tyrosine family as signal integrators.

Abstract: ErbB receptor tyrosine kinases (RTKs) and their ligands have important roles in normal development and in human cancer. Among the ErbB receptors only ErbB2 has no direct ligand; however, ErbB2 acts as a co-receptor for the other family members, promoting high affinity ligand binding and enhancement of ligand-induced biological responses. These characteristics demonstrate the central role of ErbB2 in the receptor family, which likely explains why it is involved in the development of many human malignancies, including breast cancer. ErbB RTKs also function as signal integrators, cross-regulating different classes of membrane receptors including receptors of the cytokine family. Cross-regulation of ErbB RTKs and cytokines receptors represents another mechanism for controlling and enhancing tumor cell proliferation.

Prospects for phosphoinositide 3-kinase inhibition as a cancer treatment.

Abstract: The phosphoinositide 3-kinases (PI3-kinases) are a family of lipid kinases that have a key role in the regulation of many cellular processes including proliferation, survival, carbohydrate metabolism, and motility There is now strong evidence that some members of the PI3-kinase family have an important role in cancer Emerging evidence for functional specialisation of PI3-kinase isoforms suggests that isoform selective inhibitors, in contrast to the existing non-selective inhibitors wortmannin and LY294002, may prove to be useful anticancer drugs

The Type 1 growth factor receptors and their ligands considered as a complex system.

Abstract: The Type 1 family of growth factors and their receptors play an important role in normal development, wound healing and in diseases such as cancer. The products of the four receptor genes and the ten genes specifying ligands interact in a complex pattern. Such systems may develop emergent properties which cannot be predicted from a reductionist analysis of the interactions of individual components. New methods of determining these higher level properties are, however, being developed. These include microscopic analysis of live cells expressing fluorescently tagged ligands, receptors and second messengers which can provide positional information on components of the system. Computational simulations of the complex interactions are being developed which can help to predict the properties of the system.

Treatment of medullary thyroid carcinoma: an update.

Abstract: Prognosis and treatment effectiveness of medullary thyroid carcinoma (MTC) are largely related to the tumour stage, so that early diagnosis represents an important goal for the management of patients. Recent advances in genetic testing have improved the clinical approach to the familial MTC syndromes. There is general agreement that the primary operation for MTC should obtain the complete removal of the neoplastic tissue in the neck, because any adjuvant treatment has never been proven to be effective. The management of residual/recurrent or metastatic MTC still remains controversial, although a multimodal approach to advanced disease may be of value in palliation or local control of tumour progression. The role of surgery, external radiotherapy, radionuclide therapy and medical treatment, including biological response modifiers and cytotoxic drugs, are reviewed and discussed.

Localization of parathyroid tumours in the minimally invasive era: which technique should be chosen? Population-based analysis of 253 patients undergoing parathyroidectomy and factors affecting parathyroid gland detection.

Abstract: A series of 253 consecutive patients with proved primary hyperparathyroidism due to parathyroid tumourswasreviewed. There were 68 (26.9%) men and 185 (73.1%) women, with a median age of 57 years (range 13–82 years). All patients, prior to successful parathyroidectomy, underwent one or more preoperative localization procedures such as: neck ultrasonography (US) in 191 (75.5%), 201 Tl/ 99m Tc-pertechnetate subtraction scintigraphy (TPS) in 144 (56.9%), CT scan in 92 (36.4%), 99m Tc-sestamibi/ 99m Tc-pertechnetate subtraction scintigraphy (MPS) in 90 (35.6%), selective venous sampling (SVS) with parathyroid hormone (PTH) assay in 30 (11.9%), and magnetic resonance imaging (MRI) in 6 (2.4%) patients. The results were compared with operative and histological findings that showed 235 (92.9%) solitary parathyroid adenomas, 13 (5.1%) carcinomas and 5 (2.0%) double adenomas. Sensitivity and positive predictive value were 82.9% and 93.8% for US, 83.6% and 91.8% for TPS, 81.3% and 98.7% for CT scan, 85.1% and 96.1% for MPS, 65.4% and 80.9% for SVS, and 80.0% and 80.0% for MRI respectively. No different results (P = NS) were found using US, TPS, MPS or CT scan, whereas SVS and MRI sensitivity was lower (P < 0.05). The combination of MPS and US was 94.0% sensitive (P < 0.05) but when TPS, CT scan or MRI were also used overall sensitivity did not improve significantly (P = NS). In conclusion, MPS should be used as the starting preoperative localization procedure, while US and MPS together represent the most reliable noninvasive localization tool. If MPS and US are negative or not in agreement, further studies are not cost-effective and the patient should undergo bilateral neck exploration.

Phytoestrogens after breast cancer.

Abstract: The current extension of the indications for adjuvant chemotherapy, which predisposes to early menopause, and the media coverage of the benefits of hormone replacement therapy (HRT) have led patients with a history of breast cancer to seek treatments for estrogen deprivation. In breast cancer survivors, most physicians avoid HRT because of concern regarding the potential promotion of growth of occult malignant cells by estrogens, due to the estrogen dependence of breast cancer. Soy phytoestrogens are being promoted as the 'natural alternative' to HRT and have been available without restrictions for several years as nutritional supplements. In this paper, data on the complex mammary effects of phytoestrogens in epidemiological studies, in in vitro studies, as well as in in vivo studies on animal carcinogenesis are reviewed. The potential benefits and risks of phytoestrogens are analyzed, and the prescription of phytoestrogens to postmenopausal women after breast cancer and the coprescription with the anti-estrogen tamoxifen are discussed. The absence of controlled trials and technical checking of extraction and titration in these preparations on 'free sale' raise a new problem in terms of public health and justify close reasoning and a cautious attitude of physicians, as well as straight information given to women, especially after breast cancer.

The management of ductal carcinoma in situ of the breast.

Abstract: Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group of lesions with diverse malignant potential. It is the most rapidly growing subgroup within the breast cancer family with more than 42 000 new cases diagnosed in the United States during 2000. Most new cases are nonpalpable and are discovered mammographically. Treatment is controversial and ranges from excision only, to excision with radiation therapy, to mastectomy. Prospective randomized trials reveal an approximate 50% reduction in local recurrence rate overall with the addition of radiation therapy to excisional surgery, but the published prospective data do not allow the selection of subgroups in whom the benefit from radiation therapy is so small that its risks outweigh its benefits. Nonrandomized single facility series suggest that age, family history, nuclear grade, comedo-type necrosis, tumor size and margin width are all important factors in predicting local recurrence and that one or more of these factors could be used to select subgroups of patients who do not benefit sufficiently from radiation therapy to merit its use. When all patients with ductal carcinoma in situ are considered, the overall mortality from breast cancer is extremely low, only about 1–2%. When conservative treatment fails, approximately 50% of all local recurrences are invasive breast cancer. In spite of this, the mortality rate following invasive local recurrence is relatively low, about 12% with eight years of actuarial follow-up. Genetic changes routinely precede morphological evidence of malignant transformation. Lessons learned from ongoing basic science research will help us to identify those DCIS lesions that are unlikely to progress and to prevent progression in the rest.

Farnesyl transferase inhibitors--a novel therapy for breast cancer.

Abstract: Inhibitors of the enzyme farnesyl protein transferase prevent a key step in the post-translational processing of the Ras protein, and were developed initially as a therapeutic strategy to inhibit cell signalling in ras-transformed cells. As more has been learnt about the biological effects of farnesyl transferase inhibitors (FTIs) on cancer cells, it is clear that tumours without oncogenic ras mutations such as breast cancer may also be targets for FTI therapy. This article reviews the rationale for the development of FTIs, focussing on early preclinical data in breast cancer models together with preliminary results from the first phase II study of an FTI in advanced breast cancer. Endocrine-Related Cancer (2001) 8 227–235

Microarrays in primary breast cancer--lessons from chemotherapy studies.

Abstract: Current development in molecular techniques has extended the opportunities to explore genetic alterations in malignant tissue. There is a need to improve prognostication and, in particular, to understand the mechanisms of treatment resistance in different tumours. Gene analyses by microarrays allow concomitant analyses of several genes in concert, providing new opportunities for tumour classification and understanding of key biological disturbances. This paper outlines our continuing studies exploring prognostic and, we hope, predictive factors in breast cancer therapy.

Oncogenic co-operation in beta-cell tumorigenesis.

Abstract: Pancreatic islet neoplasms are rare endocrine tumours. The most common type is of beta-cell origin and is known as insulinoma, which can be either benign or malignant. The majority of insulinomas arise sporadically, but a small proportion develop as part of the hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. As for many human tumours, the genetic events that occur during the initiation and progression of insulinoma are poorly known. The men1 gene product, menin, is deficient in most hereditary cases, but is not obviously affected in the majority of sporadic tumours. Activation of the proto-oncogenes c-myc and ras has been observed during malignant progression, but their role in tumour initiation remains unproven. To address these questions, transgenic mouse models have been increasingly used to explore molecular and genetic events that might also precipitate human neoplasia. Transgenic mice expressing SV40 large T-antigen (Tag) oncogene in beta-cells develop tumours in a multi-stage progression from hyperplasia, angiogenesis, to solid encapsulated tumours. However, Tag, which inactivates the key tumour suppressors p53 and Rb, is not known to be involved in the pathogenesis of human insulinoma. The proto-oncogene, c-myc is implicated in beta-cell growth in both diabetes and tumorigenesis. Activation of Myc appears to be an early event in progression of human insulinoma. The effect of deregulated Myc expression on adult beta-cells in vivo has recently been investigated by developing transgenic mouse models in which the activity of Myc can be regulated ectopically. Although Myc activation initially promotes both proliferation and apoptosis in pancreatic beta-cells, apoptosis is the predominant outcome, giving rise to islet involution and diabetes. Importantly, inhibiting Myc-induced apoptosis (by co-expression of Bcl-x(L)) leads to significantly enlarged islets, many becoming highly vascularized, hyperplastic and invasive. These results suggest that, in the pancreatic beta-cells, early suppression of apoptosis is essential for the survival of Myc-activated beta-cells and islet neoplasia.

An adenoviral vector expressing functional heterogeneous proteins herpes simplex viral thymidine kinase and human interleukin-2 has enhanced in vivo antitumor activity against medullary thyroid carcinoma.

Abstract: To explore a more efficient multi-gene antitumor treatment, we developed an adenoviral vector expressing both herpes simplex virus thymidine kinase (HSVtk) and human interleukin-2 (hIL-2) (AdCMVTKhIL2). Production of hIL-2 is expected to augment antitumor T cell and natural killer cell activity. Two separate cassettes expressing HSVtk and hIL-2, each under the control of the human cytomegalovirus (CMV) immediate early gene promoter, were inserted into the early 1 region of adenovirus type 5. This vector showed similar direct cytotoxicity towards infected rat medullary thyroid carcinoma (rMTC) cells as did the single gene vector, AdCMVtk. rMTC cells infected with the virus in vitro showed high sensitivity to ganciclovir. After infection with AdCMVTKhIL2 at 100 m.o.i. for 1 h, more than 20 000 U hIL-2 were produced during 24 h by 1× 10 6 rMTC cells on day 2 and day 3. hIL-2 was also detected in the supernatants of primary cultures from tumors treated in vivo by the AdCMVTKhIL2 vector. Infected cells lost their tumorigenicity when transplanted subcutaneously into syngeneic rats, whereas all control animals developed tumors. More than 63% of tumors (19 out of 30 treated tumors) were destroyed when AdCMVTKhIL2 was injected intratumorally, compared with 38% when tumors were treated with AdCMVIL2, and 12% when treated with AdCMVtk, indicating an antitumor effect superior to that of each single vector given alone at the same dosage. These results indicate that the AdCMVTKhIL2 vector efficiently produces both HSVtk and hIL-2, and provides an enhanced antitumor activity. Endocrine-Related Cancer (2001) 8 315–325

Studies of epidermal growth factor receptor inhibition in breast cancer.

Abstract: Until recently, there has been little knowledge on the growth control of oestrogen receptor (ER)-negative ductal carcinoma in situ (DCIS) and invasive breast cancer. The recent development of DCIS models, such as transgenic mice, cell-line xenograft models and, importantly, in vivo human DCIS xenograft models has facilitated the investigation and understanding of the control of growth of early pre-invasive breast lesions. Recent studies have shown that ER-negative DCIS, unlike ER-positive DCIS, is hormone independent and does not respond to anti-oestrogen treatment. Moreover, DCIS of the comedo type utilises type I tyrosine kinase growth factors, such as epidermal growth factor receptor (EGFR) and c-erbB-2, in receptor signalling for growth. New data underscore the importance of EGFR as the major modulating growth factor receptor in the control of proliferation in the breast. Pre-clinical studies performed on human DCIS xenografts in nude mice suggest a potential role for EGFR tyrosine kinase inhibitors (EGFR-TKIs). More specifically, ZD1839, a novel orally active and selective EGFR-TKI, has been shown to produce a response in DCIS through a decrease in epithelial proliferation. These findings have enhanced our knowledge of signal transduction pathways in cancer and indicate that tyrosine kinase blockade of EGFR has potential for the treatment and chemoprevention of DCIS. It is hoped that further advances in this area and evaluation of EGFR-TKIs in Phase II/III clinical trials will allow their therapeutic potential as anticancer agents to be appreciated.

New approaches to surgery for breast cancer.

Abstract: The surgical management of breast cancer is rapidly evolving towards less invasive procedures. Alternative biopsy techniques, including fine-needle aspiration and core needle biopsy, are replacing excisional biopsy as the treatment standard. Breast conservation therapy is now widely used in place of mastectomy, both for small tumors and for larger tumors that have been downstaged through induction chemotherapy. Less invasive procedures for axillary treatment such as lymphatic mapping and sentinel lymph-node biopsy are being explored in an effort to avoid the morbidity associated with axillary lymph-node dissection. For women who still prefer or need to receive a mastectomy, immediate breast reconstruction with autologous tissue provides an excellent cosmetic outcome that is oncologically sound. This is especially appealing to high-risk women who opt to have a prophylactic mastectomy. High-risk women are also being offered the option of receiving chemopreventive treatment that may reduce their lifetime risk of cancer by almost 50%. These new, less invasive approaches require the close cooperation of a team of physicians, including surgeons, pathologists, radiologists, and medical and radiation oncologists. Endocrine-Related Cancer (2001) 8 265–286

Cardiac metastasis from primary anaplastic thyroid carcinoma: report of three cases and a review of the literature

Abstract: Background: Clinically evident cardiac metastases from malignant neoplasms are uncommon. The frequency of thyroid metastasis to the heart is very low. To our knowledge, over the last 20 years only a few cases have been reported in the entire literature. Metastatic cardiac involvement occurs most often during the terminal stage. Patients: We present three cases of anaplastic thyroid cancer with metastatic involvement of the heart. Results: Two of the patients died from cardiac problems. The absence of early symptoms makes the clinical diagnosis of metastatic carcinoma difficult. Conclusions: Anaplastic thyroid cancer is an aggressive cancer with a dismal prognosis. It should be borne in mind as a source of cardiac metastasis and a cause of cardiac death. Endocrine-Related Cancer (2001) 8 71–73

Fibroblast growth factor signalling in mouse mammary gland development.

Abstract: Fibroblast growth factors (Fgfs) and their receptors are important intercellular signalling molecules involved in many aspects of animal development. The aberrant expression of the Fgfs or the inappropriate activation of their cell surface receptors have been implicated in tumorigenesis. Here, we describe the evidence that as well as playing a critical role in the formation of the mammary primordia during embryogenesis, signalling by Fgfs is necessary for optimal lobuloalveolar development of the mouse mammary gland during pregnancy.