Use of MarginProbe as an adjunct to standard operating procedure does not significantly reduce re-excision rates in breast conserving surgery.

PURPOSE: A positive margin after breast conserving surgery has consistently been shown to be a significant predictor for ipsilateral breast tumor recurrence. Currently, there is no standard for intraoperative margin assessment during lumpectomy, and up to 20% of cases result in positive margins. MarginProbe is a device that provides real-time evaluation of lumpectomy margins during surgery. The aim of this study was to evaluate the impact of MarginProbe as an adjunct to standard operating procedure (SOP). METHODS: Patients diagnosed with breast cancer scheduled for breast conserving surgery were consented for intraoperative use of MarginProbe. Shaved margins were excised based on margin assessment using the surgeon's SOP which included specimen radiography and gross pathologic examination, and feedback from the device. The primary endpoint was re-excision rate. Secondary endpoints included sensitivity, specificity, false-positive and negative rates. RESULTS: Of the 60 breast cancers, initial histologically close/positive margins were identified in 18 patients (30%). The re-excision rate in the overall cohort was 6.6%, compared to a historical re-excision rate of 8.6% (p < 0.01). Based on 360 measurement sites, MarginProbe demonstrated a sensitivity of 67% and specificity of 60%, with a positive predictive value of 16%, and of negative predictive value of 94%, which was similar to the accuracy of SOP. CONCLUSIONS: MarginProbe performs equally as well as specimen radiography and gross pathologic examination. In this setting where the baseline re-excision rate was low, the use of MarginProbe as an adjunct to SOP resulted in a small 2% absolute reduction in re-excision rate.

The role of chemotherapy and targeted therapy in the treatment of intracranial meningioma.

PURPOSE OF REVIEW: Outline current chemotherapy and targeted therapy treatments for intracranial meningiomas. RECENT FINDINGS: At present, there is no defined role for adjuvant chemotherapy for meningioma of any grade following initial diagnosis. In the subpopulation of patients with an unresectable meningioma and refractory to radiotherapy, hormonal chemotherapy-targeted therapy may be prescribed. Notwithstanding limited data, hydroxyurea, somatostatin analogues and interferon-α have been modestly successful in patients with recurrent meningiomas. Emerging targeted therapies, particularly angiogenic inhibitors, may prove useful in refractory meningiomas as recently demonstrated with sunitinib and novel somatostatin analogues. SUMMARY: A number of challenges are apparent with respect to the use of chemotherapy or targeted therapy for intracranial meningioma. First, there is very limited published literature that provides compelling evidence from which to determine appropriate therapy. Second, there is a paucity of clinical trials for patients with recurrent meningioma. Third, there remains a lack of agreement or standardization as to what constitutes a meaningful response to medical therapy recognizing these metrics differ between low-grade and high-grade recurrent meningioma. As a consequence, there remains a significant unmet need in neuro-oncology for defining the role of chemotherapy or targeted therapy in recurrent meningioma.

Vascular Normalization to Improve Treatment of COVID-19: Lessons from Treatment of Cancer.

The dramatic impact of the COVID-19 pandemic has resulted in an "all hands on deck" approach to find new therapies to improve outcomes in this disease. In addition to causing significant respiratory pathology, infection with SARS-CoV-2 (like infection with other respiratory viruses) directly or indirectly results in abnormal vasculature, which may contribute to hypoxemia. These vascular effects cause significant morbidity and may contribute to mortality from the disease. Given that abnormal vasculature and poor oxygenation are also hallmarks of solid tumors, lessons from the treatment of cancer may help identify drugs that can be repurposed to treat COVID-19. Although the mechanisms that result in vascular abnormalities in COVID-19 are not fully understood, it is possible that there is dysregulation of many of the same angiogenic and thrombotic pathways as seen in patients with cancer. Many anticancer therapeutics, including androgen deprivation therapy (ADT) and immune checkpoint blockers (ICB), result in vascular normalization in addition to their direct effects on tumor cells. Therefore, these therapies, which have been extensively explored in clinical trials of patients with cancer, may have beneficial effects on the vasculature of patients with COVID-19. Furthermore, these drugs may have additional effects on the disease course, as some ADTs may impact viral entry, and ICBs may accelerate T-cell-mediated viral clearance. These insights from the treatment of cancer may be leveraged to abrogate the vascular pathologies found in COVID-19 and other forms of hypoxemic respiratory failure.

Combination of methylselenocysteine with tamoxifen inhibits MCF-7 breast cancer xenografts in nude mice through elevated apoptosis and reduced angiogenesis.

To investigate the therapeutic effect of methylselenocysteine (MSC) combined with tamoxifen in MCF-7 breast cancer xenograft and the underlying mechanisms. MCF-7 breast cancer xenograft was established in ovariectomized female athymic nude mice and treated with tamoxifen and/or MSC. Tumor size was measured twice a week. Immunohistochemistry and TUNEL assays were used to measure ERalpha expression, ERalpha target genes (progesterone receptor (PR) and cyclin D1 expression), Ki-67 index, apoptosis and microvessel density. Combined treatment with tamoxifen and MSC synergistically inhibited tumor growth compared to MSC alone and tamoxifen alone. MSC alone or MSC + tamoxifen significantly reduced ERalpha, PR and cyclin D1, Ki67 index and microvessel density while increasing apoptosis in tumor tissues. These findings demonstrate synergistic growth inhibition of ERalpha positive breast cancer xenografts by combination of tamoxifen with organic selenium compounds. Organic selenium may provide added benefit when combined with tamoxifen in adjuvant therapy or prevention.

Clioquinol, a therapeutic agent for Alzheimer's disease, has proteasome-inhibitory, androgen receptor-suppressing, apoptosis-inducing, and antitumor activities in human prostate cancer cells and xenografts.

Tumor growth and metastasis depend on angiogenesis that requires the cofactor copper. Consistently, high levels of copper have been found in many types of human cancers, including prostate, breast, colon, and lung. Recent studies suggest that copper could be used as a novel selective target for cancer therapies. Clioquinol is capable of forming stable complexes with copper and currently used in clinics for treatment of Alzheimer's disease. Most recently, it has been reported that clioquinol possesses antitumor effects. However, the underlying molecular mechanism is unclear. We report here that after binding to copper, clioquinol can inhibit the proteasomal chymotrypsin-like activity, repress androgen receptor (AR) protein expression, and induce apoptotic cell death in human prostate cancer LNCaP and C4-2B cells. In addition, clioquinol alone exhibits similar effects in prostate cancer cell lines with elevated copper at concentrations similar to those found in patients. Addition of dihydrotestosterone did not affect clioquinol-mediated proteasome inhibition in both prostate cancer cell lines. However, dihydrotestosterone partially inhibited clioquinol-induced AR suppression and apoptosis only in androgen-dependent LNCaP cells. Animal studies show that clioquinol treatment significantly inhibits the growth of human prostate tumor C4-2B xenografts (by 66%), associated with in vivo proteasome inhibition, AR protein repression, angiogenesis suppression, and apoptosis induction. Our study provides strong evidence that clioquinol is able to target tumor proteasome in vivo in a copper-dependent manner, resulting in formation of an active AR inhibitor and apoptosis inducer that is responsible for its observed antiprostate tumor effect.

Progestin-dependent progression of human breast tumor xenografts: a novel model for evaluating antitumor therapeutics.

Recent clinical trials indicate that synthetic progestins may stimulate progression of breast cancer in postmenopausal women, a result that is consistent with studies in chemically-induced breast cancer models in rodents. However, progestin-dependent progression of breast cancer tumor xenografts has not been shown. This study shows that xenografts obtained from BT-474 and T47-D human breast cancer cells without Matrigel in estrogen-supplemented nude mice begin to regress within days after tumor cell inoculation. However, their growth is resumed if animals are supplemented with progesterone. The antiprogestin RU-486 blocks progestin stimulation of growth, indicating involvement of progesterone receptors. Exposure of xenografts to medroxyprogesterone acetate, a synthetic progestin used in postmenopausal hormone replacement therapy and oral contraception, also stimulates growth of regressing xenograft tumors. Tumor progression is dependent on expression of vascular endothelial growth factor (VEGF); growth of progestin-dependent tumors is blocked by inhibiting synthesis of VEGF or VEGF activity using a monoclonal anti-VEGF antibody (2C3) or by treatment with PRIMA-1, a small-molecule compound that reactivates mutant p53 into a functional protein and blocks VEGF production. These results suggest a possible model system for screening potential therapeutic agents for their ability to prevent or inhibit progestin-dependent human breast tumors. Such a model could potentially be used to screen for safer antiprogestins, antiangiogenic agents, or for compounds that reactivate mutant p53 and prevent progestin-dependent progression of breast disease.

A phase II study of sorafenib in patients with chemo-naive castration-resistant prostate cancer.

BACKGROUND: The purpose of this trial was to evaluate the antitumor activity of sorafenib, a multikinase inhibitor of cell proliferation and angiogenesis, in patients with castration-resistant prostate cancer. PATIENTS AND METHODS: This was a multicenter, two-stage, phase II study. Sorafenib 400 mg was administered orally twice daily continuously. Primary end point was prostate-specific antigen (PSA) 'response' defined as a > or =50% decrease for > or =4 weeks. RESULTS: In all, 28 patients were enrolled. Eastern Cooperative Oncology Group performance status was zero or one in 19 and 9 patients. Two patients had no metastases, and 26 had bone and/or lymph node disease. A median of two cycles (range 1-8) was delivered. Adverse events were typical for sorafenib. The PSA response rate was 3.6% [95% confidence interval (CI) 0.1% to 18.3%] with response occurring in one patient (baseline = 10 000 and nadir = 1643 microg/l). No measurable disease responses occurred in eight patients. Time to PSA progression was 2.3 months (95% CI 1.8-6.4). Of 16 patients who discontinued sorafenib and then did not receive any immediate therapy, 10 had postdiscontinuation PSA declines of 7%-52%. CONCLUSIONS: Sorafenib has limited activity using current PSA criteria. The declines in PSA observed on treatment discontinuation indicate an effect on PSA production/secretion. Further study may be warranted but needs to consider the limitations of PSA as an indicator of progression and response.

Differential expression of angiopoietin-2 and vascular endothelial growth factor in androgen-independent prostate cancer models.

OBJECTIVE: To investigate the relationship between microvessel density (MVD), blood vessel morphology and the expression of angiopoietin (Ang)-1, Ang-2, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (Tie)-2, and vascular endothelial growth factor (VEGF) in androgen-dependent (AD) and androgen-independent (AI) prostate cancer models, to gain insight into the regulation of angiogenesis at different stages of prostate cancer. MATERIALS AND METHODS: MVD and blood vessel morphology were evaluated by CD34 immunohistochemical staining. The mRNA and protein secretion of the Angs, Tie-2 and VEGF were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assays, respectively, in LNCaP (AD) and LNCaP-19, C4-2, C4-2B4 and PC-3 (AI) prostate cancer xenografts in mice. RESULTS: LNCaP, C4-2 and C4-2B4 xenografts had high expression of Ang-2 and VEGF, similar MVD and blood vessel morphology. However, the most angiogenic cell line LNCaP-19 expressed low levels of both factors and had different vessel morphology. PC-3 xenografts had a similar MVD to LNCaP, C4-2 and C4-2B4, but the Ang-2 and VEGF expression as well as the vessel morphology were similar to LNCaP-19. CONCLUSION: The differences in MVD, blood vessel morphology and the expression of Ang-2 and VEGF show that prostate cancer cells display angiogenic heterogeneity, which indicates different roles of these factors in the regulation of angiogenesis in different stages of prostate cancer.

Estrogen induces lung metastasis through a host compartment-specific response.

Direct proliferative effects of estrogen (E(2)) on estrogen receptor-positive tumors are well documented; however, the potential for E(2) to mediate effects selective for the host (i.e., angiogenesis, vascular permeability, or stromal effects), which influence tumor growth and/or metastasis, has received less attention. In this study, we examine the capacity for E(2) to promote tumor growth and/or metastasis independent of direct effects on tumor cells. In these studies, we distinguish host versus tumor compartment components of E(2) action in tumor growth and metastasis by analysis of E(2)-nonresponsive tumor cells implanted in ovariectomized (OVX) mice that contain s.c. implants of placebo (OVX) or E(2)-containing slow-release pellets (OVX + E(2)). We show that the D121 lung carcinoma cell line is E(2)-nonresponsive, and following s.c. implantation in OVX versus OVX + E(2) mice, E(2) action on the host compartment leads to an increase in spontaneous metastasis but not primary tumor growth or neovascularization. Similarly, experimental lung metastasis of E(2)-nonresponsive 4T1 mammary carcinoma cells also leads to increased tumor burden in the lungs of OVX + E(2) mice. These results suggest that the E(2) status of the host compartment influences late steps in tumor cell metastasis that can provide important insights into the role of E(2) in the tumor versus host compartments.

Molecularly targeted therapeutics for breast cancer.

Thomas Beatson's celebrated description in 1896 of bilateral oophorectomy as effective therapy for premenopausal breast cancer could be considered as the first demonstration of response of any cancer to a 'targeted therapy.' At that time, however, the understanding of the mechanism of the intervention was minimal. In recent years a host of new rationally designed, molecularly targeted cancer therapies have been introduced from both large pharmaceutic and small biotechnology companies, and the portfolio of new targeted treatments in the pipeline appears to be unending. The existence of this array of potential new therapies is the result of a prodigious effort in the researching and defining of the molecular components of the cancer phenotype, and the subsequent rational design of agents to target candidate pathways. Experience with endocrine therapy has shown that targeted therapies require the target to be not merely expressed in the cancer phenotype, but important in regulating growth of cancer cells. We may well look back at many of the current targeted therapy trials as unrealistically simplistic in failing to adequately and define the target phenotype. This approach risks rejecting highly active treatments for a small subgroup of a study population where minimal activity is present for the majority. The future for breast cancer therapy is promising, but it is important to be prepared for disappointment, as early success in animal models cannot guarantee a successful human therapy. Stunning results such as the adjuvant trastuzumab trials are likely to remain the exceptions rather that the rule, and most gains will be modest advances. A better understanding of the molecular biology of cancer may also aid in guiding the most appropriate use of existing therapies such as conventional chemotherapy. This knowledge will facilitate the rational selection of drug combinations and/or sequencing based on their mechanisms of action at a molecular level. The aim of this paper is to review the current state-of-the-art in novel targeted therapies for breast cancer based on an understanding of this disease at the molecular level, with particular reference to those agents entering the clinic.

Molecular alterations in the pathogenesis of endometrial adenocarcinoma. Therapeutic implications.

Molecular genetic evidence indicates that endometrial carcinoma likely develops as the result of a multistep process of oncogene activation and tumor suppressor gene inactivation. These molecular alterations appear to be specific for Type I (endometrioid) and Type II (non endometrioid) cancers. Type I cancers are characterized by mutation of PTEN, KRAS2, defects in DNA mismatch repair, as evidenced by the microsatellite instability phenotype, and a near diploid karyotype. Type II cancers often contain mutations of TP53 and Her-2/neu and are usually nondiploid. The clinical value of many of these molecular markers is now being tested and it may help to refine diagnosis and establish an accurate prognosis. Furthermore, some of these tumor biomarkers constitute the targets for emerging therapies. Transtuzumab against Her-2/neu and bevacizumab against VEGF overexpressing carcinomas are among the promising novel treatments. Additional translational research is needed to identify molecular and genetic alterations with potential for therapeutic interventions.

Tumor oxygenation in hormone-dependent tumors during vascular endothelial growth factor receptor-2 blockade, hormone ablation, and chemotherapy.

Tumor oxygenation is critical for tumor survival as well as for response to therapy, e.g., radiation therapy. Hormone ablation therapy in certain hormone-dependent tumors and antiangiogenic therapy lead to vessel regression and have also shown beneficial effects when combined with radiation therapy. These findings are counterintuitive because vessel regression should reduce oxygen tension (pO2) in tumors, decreasing the effectiveness of radiotherapy. Here we report on the dynamics of pO2 and oxygen consumption in a hormone-dependent tumor following hormone ablation and during treatment with an anti-VEGFR-2 monoclonal antibody (mAb) or a combination of doxorubicin and cyclophosphamide; the latter combination is not known to cause vessel regression at doses used clinically. Androgen-dependent male mouse mammary carcinoma (Shionogi) was implanted into transparent dorsal skin-fold chambers in male severe combined immunodeficient mice. Thirteen days after the tumors were implanted, mice were treated with antiangiogenic therapy (anti-VEGFR-2 mAb, 1.4 mg/30 g body weight), hormone ablation by castration, or doxorubicin (6.5 mg/kg every 7 days) and cyclophosphamide (100 mg/kg every 7 days). A non-invasive in vivo method was used to measure pO2 profiles and to calculate oxygen consumption rates (Q(O2)) in tumors. Tumors treated with anti-VEGFR-2 mAb exhibited vessel regression and became hypoxic. Initial vessel regression was followed by a "second wave" of angiogenesis and increases in both pO2 and Q(O2). Hormone ablation led to tumor regression followed by an increase in pO2 coincident with regrowth. Chemotherapy led to tumor growth arrest characterized by constant Q(O2) and elevated pO2. The increased pO2 during anti-VEGFR-2 mAb and hormone ablation therapy may explain the observed beneficial effects of combining antiangiogenic or hormone therapies with radiation treatment. Thus, understanding the microenvironmental dynamics is critical for optimal scheduling of these treatment modalities.

Overexpression of vascular endothelial growth factor by MCF-7 breast cancer cells promotes estrogen-independent tumor growth in vivo.

Alteration of the phenotype of breast cancers from estrogen-dependent to estrogen-independent growth often leads to the failure of antiestrogenic tumor therapies. We report that overexpression of vascular endothelial growth factor (VEGF) by estrogen-dependent MCF-7 breast cancer cells could abolish estrogen-dependent tumor growth in ovariectomized mice. In the absence of estrogen, MCF-7 VEGF-expressing tumors with increased vessel density showed growth kinetics similar to, or even greater than, that of parental MCF-7 tumors with estrogen supplementation. Overexpression of VEGF by MCF-7 cells or treatment on parental MCF-7 cells with recombinant VEGF also stimulated cell proliferation in culture. Our data suggest that VEGF stimulation of MCF-7 tumor angiogenesis and growth is mediated by both autocrine and paracrine mechanisms.

Sex steroid-dependent angiogenesis in uterine endometrial cancers.

In general, tumors induce angiogenic factors specific to them, which leads to angiogenesis with advancement. However, angiogenesis in uterine endometrial cancers is complicated because hormone dependency in growth also modifies the angiogenic potential. Therefore, anti-angiogenic therapy for tumor dormancy in uterine endometrial cancers must be thoroughly considered. The upstream of vascular endothelial growth factor (VEGF) gene conserves estrogen-responsive elements. Progesterone primed with estrogen induces thymidine phosphorylase (TP) in uterine endometrium. Sex steroid-dependent VEGF and TP are highly expressed in cases of early stage and well-differentiated uterine endometrial cancers, and basic fibroblast growth factor (bFGF) in cases of advanced and poorly differentiated uterine endometrial cancers. A transcriptional factor for angiogenesis, ETS-1, is linked to VEGF in well-differentiated uterine endometrial cancers, and to bFGF in poorly differentiated uterine endometrial cancers. Therefore, even if dedifferentiation and angiogenic switching occur due to advancement and long-term hormone therapy, the inhibition of ETS-1 along with main angiogenic factors might be an effective strategy to suppress uterine endometrial cancers as a novel anti-angiogenic therapy.

Combination antiangiogenic and androgen deprivation therapy for prostate cancer: a promising therapeutic approach.

PURPOSE: Androgen ablation therapy leads to mild regression or stabilization of prostate cancer, followed by progression to the fatal androgen-independent state. Whereas androgen ablation diminishes tumor angiogenesis by suppressing vascular endothelial growth factor (VEGF) production, androgen-independent disease is marked by androgen-independent VEGF expression. We examined combined androgen ablation and inhibition of VEGF signaling in an androgen-sensitive human prostate cancer xenograft model (LNCaP) that is known to develop androgen-independent growth after androgen ablation. EXPERIMENTAL DESIGN: N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine (ZD6474) is an orally active inhibitor of VEGF receptor tyrosine kinase activity, with additional activity against epidermal growth factor receptor tyrosine kinase. ZD6474 (50 mg/kg/d, per os) was administered to groups of castrated and noncastrated athymic mice bearing established (4-616 mm3) LNCaP xenografts. To evaluate the extent of tumor regrowth after ZD6474, treatment was stopped after 40 days of continuous dosing, and subsequent tumor growth was monitored. Prostate-specific antigen expression was assessed to determine the effect of ZD6474 on androgen-regulated genes. RESULTS: In comparison with orchiectomy, ZD6474 treatment produced greater tumor growth inhibition (P < 0.001), inducing complete cytostasis for the duration of dosing. An analysis of serum prostate-specific antigen concentration and tumor weight indicated that ZD6474 did not have a direct effect on androgen-related gene expression. Combination therapy (castration plus ZD6474) produced a comparable therapeutic effect to treatment with ZD6474 alone (in noncastrated mice), for the duration of ZD6474 administration. However, when ZD6474 treatment was discontinued, the rate of tumor regrowth was significantly less in the combination group. Tumors from mice receiving combined treatment were also found to be more necrotic than tumors from mice receiving either androgen ablation or ZD6474 alone. CONCLUSIONS: These data indicate that inhibition of VEGF signaling produces a highly significant inhibition of tumor growth in a human androgen-dependent prostate tumor model, which far exceeds that produced by androgen ablation alone. However, when ZD6474 treatment is removed, concurrent androgen ablation produces a greater inhibition of tumor regrowth than is observed in mice without androgen ablation. Increased necrosis observed in tumors from orchiectomized mice receiving ZD6474 also suggests benefit from combining anti-androgen and anti-VEGF signaling approaches.

A long pentraxin-3-derived pentapeptide for the therapy of FGF8b-driven steroid hormone-regulated cancers.

Fibroblast growth factor-8b (FGF8b) affects the epithelial/stromal compartments of steroid hormone-regulated tumors by exerting an autocrine activity on cancer cells and a paracrine pro-angiogenic function, thus contributing to tumor progression. The FGF8b/FGF receptor (FGFR) system may therefore represent a target for the treatment of steroid hormone-regulated tumors. The soluble pattern recognition receptor long pentraxin-3 (PTX3) binds various FGFs, including FGF2 and FGF8b, thus inhibiting the angiogenic and tumorigenic activity of androgen-regulated tumor cells. Nevertheless, the complex/proteinaceous structure of PTX3 hampers its pharmacological exploitation. In this context, the acetylated pentapeptide Ac-ARPCA-NH2 (ARPCA), corresponding to the N-terminal amino acid sequence PTX3(100-104), was identified as a minimal FGF2-binding peptide able to antagonize the biological activity of FGF2. Here, we demonstrate that ARPCA binds FGF8b and inhibits its capacity to form FGFR1-mediated ternary complexes with heparan sulphate proteoglycans. As a FGF8b antagonist, ARPCA inhibits FGFR1 activation and signalling in endothelial cells, hampering the angiogenic activity exerted in vitro and in vivo by FGF8b. Also, ARPCA suppresses the angiogenic and tumorigenic potential of prototypic androgen/FGF8b-dependent Shionogi 115 mammary carcinoma cells and of androgen/FGF8b/FGF2-dependent TRAMP-C2 prostate cancer cells. In conclusion, ARPCA represents a novel FGF8b antagonist with translational implications for the therapy of steroid hormone-regulated tumors.

TZT-1027 elucidates antitumor activity through direct cytotoxicity and selective blockade of blood supply.

BACKGROUND: TZT-1027 is a newly developed antitumor agent derived from dolastatin 10. MATERIALS AND METHODS: The in vitro activity of TZT-1027 on MCF-7 and R-27 cells was evaluated by MTT assay. TZT-1027 1 mg/kg/week was administered i.v. for 4 weeks into nude mice bearing MCF-7 and R-27. Subsequently, primary cultured cells from xenografts were also used for CD-DST. Two mg of TZT-1027 or 40 mg docetaxel per kg were injected i.v. into nude mice bearing R-27. 0.2% Evans blue was injected to assess the blood flow. RESULTS: TZT-1027 suppressed the in vitro growth of MCF-7 cells, while R-27 cells were resistant to TZT-1027, although its in vivo antitumor activity was remarkable. TZT-1027 blockaded R-27 tumor blood flow immediately after injection; blood flow was not affected by docetaxel. CONCLUSION: TZT-1027 exerts its antitumor activity through direct cytotoxicity against MCF-7 cells and through selective blockade of tumor blood flow against R-27 cells.

Inhibitory effect of TNP-470, a new anti-angiogenic agent, on the estrogen induced rat pituitary tumors.

An angiogenic inhibitor, TNP-470, is an analogue of fumagillin. This study reports the effects of TNP-470 and bromocriptine on the normal pituitary glands and estrogen-induced rat pituitary tumors. TNP-470 inhibited the increase of normal pituitary weight and the tumorigenesis induced by estrogen. The decreased labelling index in the pituitary cells, showed that TNP-470 may suppress the activity of cell proliferation as the result of anti-angiogenesis. Combination treatment with TNP-470 and bromocriptine was much more effective than TNP alone. These results suggest that TNP-470 is a potentially beneficial drug for pituitary tumors.

[Antiangiogenesis therapy and hormone therapy--their resemblance and applications of prognostic and predictive factors].

Many new ideas to control tumor angiogenesis are now being tested in clinical trials. In considering strategies for clinical development of antiangiogenesis treatment, that of endocrine therapy might be particularly useful as a model. Endocrine therapy is a unique treatment used only for hormone-dependent tumors; however, its clinical fruits are exceptional in the entire history of cancer therapy. It is now clearly proven that long-term continuous treatment with antihormones brings a magnificent survival benefit for primary breast cancer patients. This benefit is tumor-phenotype oriented, where the hormone receptor is characterized as a potent predictive factor. Antiangiogenesis treatments seem to have several similarities with endocrine therapy, in that both treatments are cytostatic, stroma-targeting, time-dependent and less effective for large tumor burdens. A combination effect with chemotherapy is often observed with both treatments, at least in animal experiments. In a sense, anti-oncogene product therapy follows endocrine therapy in clinical development. Although antiangiogenesis treatments should be developed based on original concepts, the successful experience of endocrine therapy may provide many hints for the development of antiangiogenesis therapy.

Luteinizing hormone, sex steroids and extracorporeal circulation - a promising link to treat retroperitoneal sarcomas. A reconsideration of cancer treatment.

Retroperitoneal sarcomas are rare and aggressive tumors with a negative prognosis as there is currently no satisfactory treatment for them. The only proven factor that can significantly increase the otherwise poor survival of sarcoma patients is the radically of resection. However, the completeness of resection is hindered by the hypervascularized nature of sarcomas and the frequent involvement of major blood vessels. In this context, we propose to operate on retroperitoneal sarcomas only with the use of extracorporeal circulation, applying vascular clamps above and below the tumor, even with short periods of hypothermic circulatory arrest in complex cases. This technique would allow the surgeon to achieve complete tumor resections, approach large blood vessels easier and perform sofisticated vascular reconstructions with no fear of hemorrhage which is fundamental to achieve a bloodless surgical field. Also, we speculate on the etiology of retroperitoneal sarcomas that appear mostly during the period of menopause/andropause. Although both estrogens and androgens have been incriminated in inducing various cancer types, including sarcomas, an endogenous estradiol cathabolyte has been shown to have anti-tumor effects. Considering that during menopause/andropause sex steroid levels actually decrease, our second working hypothesis is that the increasing follicle-stimulating hormone (FSH) and especially luteinizing hormone (LH) levels, together with the relative estrogen/androgen imbalance, may be the triggering cause. Also, a certain level of estrogens (Methoxyestradiol) may be essential in limiting tumor development and dedifferentiation. Given that extragonadal sarcomas appear to behave as endocrine tumors, a targeted hormonal therapy, together with controlled radical resections in complex cases of tumor vascular involvement, would certainly provide a strong link to both prevention and treatment of retroperitoneal sarcomas and even of cancer in general.