Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials

Johnson, Jill; Decker, Shannon; Zaharevitz, Daniel; Rubinstein, Larry; Venditti, John M.; Schepartz, Saul A.; Kalyandrug, Sivaram; Christian, Michaele C.; Arbuck, Susan G.; Hollingshead, Melinda G.; Sausville, Edward A.

doi:10.1054/bjoc.2001.1796

Cited by 765 publications

(523 citation statements)

References 7 publications

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“…This work again implicates the collage network and collagen-binding GAGs as factors in hindering the interstitial diffusion of macromolecules. Multicellular spheroids and multilayer cellular sandwiches/ membranes are being used to test the penetrability and effectiveness of therapeutics (Fracasso and Colombatti, 2000;Padron et al, 2000;Johnson et al, 2001). Since these in vitro systems do not have the host stromal cells, the present work shows that caution must be exercised in extrapolating the results obtained from these systems to tumours in vivo.…”

Section: Discussionmentioning

confidence: 91%

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

et al. 2002

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The tumour extracellular matrix acts as a barrier to the delivery of therapeutic agents. To test the hypothesis that extracellular matrix composition governs the penetration rate of macromolecules in tumour tissue, we measured the diffusion coefficient of nonspecific IgG in three rhabdomyosarcoma subclones growing as multicellular spheroids in vitro or as subcutaneous tumours in dorsal windows in vivo. In subcutaneous tumours, the diffusion coefficient decreased with increasing content of collagen and sulphated glycosaminoglycans. When grown as multicellular spheroids, no differences in either extracellular matrix composition or diffusion coefficient were found. Comparison of in vitro vs in vivo results suggests an over-riding role of host stromal cells in extracellular matrix production subjected to modulation by tumour cells. Penetration of therapeutic macromolecules through tumour extracellular matrix might thus be largely determined by the host organ. Hence, caution must be exercised in extrapolating drug penetrability from spheroids and multilayer cellular sandwiches consisting of only tumour cells to tumours in vivo. British Journal of Cancer (2002) The extracellular matrix (ECM) is a potent barrier to the delivery and penetration of complex biopharmaceuticals such as monoclonal antibodies, therapeutic proteins, or genes. Due to the elevated interstitial fluid pressure in tumours , the therapeutic agents must reach the tumour cells by interstitial diffusion. It is not clear whether the network of fibrillar collage or the glycosaminoglycan (GAG) gel plays the most important role in limiting the diffusion of macromolecules through the ECM, and what the role of the host stromal cells is. Netti et al (2000) found that the amount of collagen in tumours correlated inversely with the diffusion coefficient of macromolecules, and collagenase treatment of the tumour increased the diffusion coefficient. Pluen et al (2001) provided further support for the role of collagen by measuring diffusion in tumours grown in subcutaneous tissue and the cranium. Hyaluronidase, on the other hand, is reported to reduce the diffusion coefficient of albumin in lung interstitium (Qiu et al, 1999).We postulated that diffusion of macromolecules is hindered both by the collagen network and by the hydrophilic gel of GAG and proteoglycans. To test this hypothesis we used three distinct clones with different degrees of differentiation and ECM (Groeschel et al, 1994) derived from a rat rhabdomyosarcoma, growing as multicellular spheroids in vitro or subcutaneously in dorsal chambers in mice in vivo. The production of ECM in tumours is the result of an active interaction between the tumour cells and stromal cells of the host (Gullino and Grantham, 1962;Knudson et al, 1984), whereas the extracellular matrix of multicellular spheroids is solely produced by the tumour cells. Comparison of the ECM composition in tumours growing as xenografts in vivo and as multicellular spheroids in vitro, is likely to reveal the influence of the host stromal ce...

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Section: Discussionmentioning

confidence: 91%

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

et al. 2002

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“…siRNAs to ERBB3 or AKT2 have recently been tested in vivo for effects on human lung adenocarcinoma xenografts, a model which has been shown to be predictive of clinical activity. 395 In three separate experiments, both siRNAs reduced by 40-80% the size of tumors formed by human lung adenocarcinoma A549 cells as xenografts in nude mice (Table 9). Nonsilencing siRNA was without significant effect.…”

Section: Erbb3 In Lung Cancermentioning

confidence: 97%

The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…Drug anti-tumor activity was evaluated as the tumor growth inhibition percentage calculated by the 1Ktreated/control tumor volume ratios (1KT/C) (Teicher 1998, Johnson et al 2001, Hollingshead 2008. Data were expressed as the median with the minimum-maximum value interval.…”

Section: Xenograft Modelmentioning

confidence: 99%

Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

Luconi¹,

Mangoni²,

Gelmini³

et al. 2010

Endocrine-Related Cancer

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Adrenocortical carcinoma (ACC) is a rare aggressive tumor with a poor prognosis. The lack of a specific and effective medical treatment is due to the poor knowledge of the mechanisms underlying tumor growth. Research on potential drugs able to specifically interfere with tumor proliferation is essential to develop more efficacious therapies. We evaluated for the first time the in vivo effect of rosiglitazone (RGZ), an anti-diabetic drug with in vitro anti-tumor properties, on ACC proliferation in a xenograft model obtained by s.c. injection of human ACC H295R cells in athymic mice. When the tumor size reached 5 mm, animals were allocated to 5 mg/kg RGZ-or water-treated groups. Tumor volume was measured twice a week. A significant reduction of tumor growth in RGZ versus control (control) group was observed and was already maximal following 17 day treatment (1KT/CZ75.4% (43.7-93.8%)). After 31 days of treatment, mice were killed and tumor analyzed. Tumor histological evaluation revealed characteristics of invasiveness, richness in small vessels and mitotic figures in control group, while RGZ group tumors presented non infiltrating borders, few vessels, and many apoptotic bodies. Tumor immunohistochemistry showed that Ki-67 was reduced in RGZ versus control group. Quantitative real-time RT-PCR demonstrated a significant reduction in the expression of angiogenic (VEGF), vascular (CD31), proliferation (BMI-1), and anti-apoptotic (Bcl-2) genes in RGZ versus control group tumors. The same inhibitory effects were confirmed in in vitro RGZ-treated H295R. Our findings support and expand the role of RGZ in controlling ACC proliferation and angiogenesis in vivo and in vitro.

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Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials

Cited by 765 publications

References 7 publications

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells

The ERBB3 receptor in cancer and cancer gene therapy

Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model

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