Time to Progression in Metastatic Breast Cancer Patients Treated With Epirubicin Is Not Improved by the Addition of Either Cisplatin or Lonidamine: Final Results of a Phase III Study With a Factorial Design

Berruti, Alfredo; Bitossi, Raffaella; Gorzegno, G.; Bottini, Alberto; Alquati, P; Matteis, A. De; Nuzzo, Francesco; Giardina, G.; Danese, Saverio; Lena, M. De; Lorusso, Vito; Farris, A.; Sarobba, Maria Giuseppa; Defabiani, E; Bonazzi, G; Castiglione, F.; Bumma, C.; Moro, G.; Bruzzi, Paolo; Dogliotti, Luigi

doi:10.1200/jco.2002.08.012

Cited by 68 publications

(39 citation statements)

References 30 publications

(7 reference statements)

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“…From October 1988 to November 1999, 791 metastatic breast cancer patients were enrolled in five consecutive phase II-III multicenter trials of first-line chemotherapy with anthracycline-based regimens [22][23][24][25][26] (Table 1). The primary aim of the studies was to determine disease response or time to progression.…”

Section: Patientsmentioning

confidence: 99%

Prognostic significance of changes in CA 15-3 serum levels during chemotherapy in metastatic breast cancer patients

Tampellini

Berruti

Bitossi

et al. 2006

Breast Cancer Res Treat

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Tumor response to first-line chemotherapy in advanced breast cancer offers prognostic information and may be used as a surrogate marker for evaluating treatment efficacy. With this study we wanted to determine whether changes in circulating serum CA 15-3 levels during chemotherapy provided additional information for prognostic prediction. Serum CA 15-3 was measured at baseline and after 3 and 6 months during anthracycline-based first-line chemotherapy in 526 patients with advanced breast cancer prospectively enrolled in five phase II-III trials. Changes in marker levels were correlated with disease response, time to progression and overall survival. In all, 336 patients attained a disease response. A significant relationship was found between disease response and CA 15-3 variations, although many individual discrepancies were also observed. At the 6-month time point, the median time to progression was 15.3 months in patients with normal marker levels throughout the study, 11.7 months in those with a CA15-3 reduction >25%, 9.6 months in those with elevated baseline CA 15-3 levels which did not change during therapy and 8.6 months in those with increased marker levels (p < 0.001). The median survival was 42.3, 29.7, 28.5, and 24.8 months, respectively (p < 0.002). The prognostic role of changes in CA 15-3 levels was maintained in the patient subset attaining disease response or stabilization to treatment (p < 0.001) and after adjusting for clinical response and major prognostic parameters in the multivariate analysis (p < 0.001). In conclusion, monitoring serum CA 15-3 levels during first-line chemotherapy in advanced breast cancer patients provides prognostic information independently from tumor response.

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Section: Patientsmentioning

confidence: 99%

Prognostic significance of changes in CA 15-3 serum levels during chemotherapy in metastatic breast cancer patients

Tampellini

Berruti

Bitossi

et al. 2006

Breast Cancer Res Treat

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“…11 These findings thus spark the interest among investigators, hoping to develop lonidamine into a potential male contraceptive. 5,12 This attempt, however, was subsequently abandoned due to the toxicity of lonidamine found in early stage cancer patients, 13,14 making it unsuitable for healthy men. However, lonidamine is still being used as an anti-cancer drug in Europe and Japan for advanced/late stage cancer patients, and it is also being actively investigated for late stage metastatic cancer treatment, 15,16 including prostatic disorders, 17 with some promising results.…”

Section: Introductionmentioning

confidence: 96%

Adjudin disrupts spermatogenesis via the action of some unlikely partners

et al. 2011

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Adjudin, 1-(2,4-dichlorobenzyl)-1H-indazole-3-carbohydrazide (formerly called AF-2364), is a potent analog of lonidamine [1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid] known to disrupt germ cell adhesion, most notably elongating and elongated spermatids, in the seminiferous epithelium of adult rat testes and thus, leads to infertility in rats. Since the population of spermatogonia and spermatogonial stem cells (SSCs) in the seminiferous tubules is not significantly reduced by the treatment of rats with adjudin, adjudin-induced infertility is highly reversible, which enables reinitiation of spermatogenesis and germ cell re-population of the voided seminiferous epithelium. Furthermore, adjudin appears to exert its effects at the testis-specific atypical adherens junction (AJ) type known as ectoplasmic specialization (ES), most notably the apical ES at the Sertoli cell-spermatid interface. Thus, the hypothalamic-pituitary-gonadal axis is not unaffected and systemic side-effects are minimal. This also makes adjudin a potential candidate for male contraceptive development. Herein, we critically evaluate recent findings in the field and provide an updated model regarding the mechanism underlying adjudin-induced apical ES disruption. In short, adjudin targets actin filament bundles at the apical ES, the hallmark ultrastructure of this testis-specific junction type not found in any other epithelia/endothelia in mammals, by suppressing the expression of Eps8 (epidermal growth factor receptor pathway substrate 8), an actin capping protein that also plays a role in actin bundling, so that actin filament bundles can no longer be maintained at the apical ES. This is concomitant with a mis-localization of Arp3 (actin-related protein 3, a component of the Arp2/3 complex that induces actin nucleation/branching) recruited by drebrin E, causing "unwanted" actin branching, further destabilizing actin filament bundles at the apical ES. Additionally, adjudin blocks the expression of PAR6 (partitioning defective protein 6) and 14-3-3 (also known as PAR5) considerably at the apical ES, disrupting the homeostasis of endocytic vesicle-mediated protein trafficking, which in turn leads to an increase in protein endocytosis. The net result of these changes destabilizes cell adhesion and induces degeneration of the apical ES, causing premature release of spermatids, mimicking spermiation.

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“…A recent phase 1 trial of 2-deoxyglucose resulted in dose-limiting toxicities at levels far below those required to elicit antitumor activity in mouse models, 10,11 whereas lonidamine has yielded superior tolerability but disappointing efficacy. 12 Intriguingly, the poor efficacy of these compounds may be explained by recent observations suggesting that glucose transport may occupy the primary ratedetermining step of glycolysis in malignant cells. 13,14 Therefore, further investigation into the molecular mechanisms underlying enhanced glucose transport rates in cancer is warranted.…”

Section: Introductionmentioning

confidence: 99%

Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy

McBrayer¹,

Cheng²,

Singhal

et al. 2012

Blood

159

176

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Multiple myeloma is one of numerous malignancies characterized by increased glucose consumption, a phenomenon with significant prognostic implications in this disease. Few studies have focused on elucidating the molecular underpinnings of glucose transporter (GLUT) activation in cancer, knowledge that could facilitate identification of promising therapeutic targets. To address this issue, we performed gene expression profiling studies involving myeloma cell lines and primary cells as well as normal lymphocytes to uncover deregulated GLUT family members in myeloma. Our data demonstrate that myeloma cells exhibit reliance on constitutively cell surface-localized GLUT4 for basal glucose consumption, maintenance of Mcl-1 expression, growth, and survival. We also establish that the activities of the enigmatic transporters GLUT8 and GLUT11 are required for proliferation and viability in myeloma, albeit because of functionalities probably distinct from whole-cell glucose supply. As proof of principle regarding the therapeutic potential of GLUT-targeted compounds, we include evidence of the antimyeloma effects elicited against both cell lines and primary cells by the FDAapproved HIV protease inhibitor ritonavir, which exerts a selective off-target inhibitory effect on GLUT4. Our work reveals critical roles for novel GLUT family members and highlights a therapeutic strategy entailing selective GLUT inhibition to specifically target aberrant glucose metabolism in cancer.

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Time to Progression in Metastatic Breast Cancer Patients Treated With Epirubicin Is Not Improved by the Addition of Either Cisplatin or Lonidamine: Final Results of a Phase III Study With a Factorial Design

Abstract: Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug's tolerability.

Cited by 68 publications

References 30 publications

Prognostic significance of changes in CA 15-3 serum levels during chemotherapy in metastatic breast cancer patients

Prognostic significance of changes in CA 15-3 serum levels during chemotherapy in metastatic breast cancer patients

Adjudin disrupts spermatogenesis via the action of some unlikely partners

Multiple myeloma exhibits novel dependence on GLUT4, GLUT8, and GLUT11: implications for glucose transporter-directed therapy

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