A Pilot Human Evaluation of a Formulation of Irinotecan and Hyaluronic Acid in 5-Fluorouracil-Refractory Metastatic Colorectal Cancer Patients

Gibbs, Peter; Brown, Tracey; Ng, Raymond; Jennens, Ross; Cinc, Edith; Pho, Minh Hue; Michael, Michael; Fox, Richard M.

doi:10.1159/000180339

Cited by 28 publications

(14 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Intra peritoneal administration of a bioconjugate of HA and paclitaxel was well tolerated and significantly decreased growth human ovarian cancer xenografts in SCID mice compared with paclitaxel alone [73,74]. More recently phase I and phase II clinical trials have demonstrated that HA and the chemotherapy drug irinotecan can be safely administered together to patients with metastatic colon cancer and improve progression free survival [75,76]. We envisage that HA oligomers could be administered intra-peritoneally Fig.…”

Section: Discussionmentioning

confidence: 95%

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Ween

Hummitzsch

Rodgers

et al. 2010

Clin Exp Metastasis

View full text Add to dashboard Cite

The assembly of pericellular matrix containing hyaluronan (HA) and versican has been shown to be a pre-requisite for proliferation and migration of mesenchymal cells. In this study, we investigated whether treatment with recombinant versican could induce the formation of a pericellular matrix by ovarian cancer cells (OVCAR-3, OVCAR-5, and SKOV-3) and promote their motility, invasion, and adhesion to peritoneal cells in vitro. We also determined whether versican-induced pericellular matrix formation and metastatic cancer cell behavior could be blocked by small HA oligosaccharides. Only combined treatment with recombinant versican and HA resulted in pericellular matrix formation by OVCAR-5 and SKOV-3 but not by OVCAR-3 cells, which lack the HA receptor, CD44. The motility of OVCAR-5 and SKOV-3 cells was significantly increased in scratch wound and chemotaxis assays following treatment with recombinant versican and HA. Versican and HA also promoted invasion of SKOV-3 and OVCAR-5 cells but had no effect on OVCAR-3 cells. We have demonstrated that exogenous HA significantly increased OVCAR-5 and SKOV-3 adhesion to peritoneal cells but adhesion was not further increased by versican treatment. Small HA oligomers (6-10 disaccharides) were able to significantly block formation of pericellular matrix by OVCAR-5 cells, as well as the increased motility and invasion induced by recombinant versican. HA oligomers also significantly blocked OVCAR-5 adhesion to peritoneal cells both in the presence and absence of exogenous HA. The dependence of CD44 for the versican and HA mediated effects were demonstrated by the inhibition of pericellular matrix formation as well as motility and invasion of OVCAR-5 cells following treatment with CD44 neutralizing antibody in the presence of versican and HA. We conclude that the acquisition of a HA/versican pericellular matrix by ovarian cancer cells increases their metastatic potential. HA oligomers can block this mechanism and are promising inhibitors of ovarian cancer dissemination.

show abstract

Section: Discussionmentioning

confidence: 95%

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Ween

Hummitzsch

Rodgers

et al. 2010

Clin Exp Metastasis

View full text Add to dashboard Cite

show abstract

“…It has also been found, however, that the enormous hydrodynamic domain encompassed by hyaluronan can be used to entrap drugs, without the need for chemical conjugation, and deliver them to CD44-expressing tumors (70). Increased safety and efficacy of irinotecan, when combined with hyaluronan using this approach, have been shown in a pilot trial with colorectal carcinoma patients (71). …”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities

Toole

2009

Clinical Cancer Research

319

304

View full text Add to dashboard Cite

Hyaluronan is a prominent component of the micro-environment in most malignant tumors and can be prognostic for tumor progression. Extensive experimental evidence in animal models implicates hyaluronan interactions in tumor growth and metastasis, but it is also evident that a balance of synthesis and turnover by hyaluronidases is critical. CD44, a major hyaluronan receptor, is commonly but not uniformly associated with malignancy, and is frequently used as a marker for cancer stem cells in human carcinomas. Multivalent interactions of hyaluronan with CD44 collaborate in driving numerous tumor-promoting signaling pathways and transporter activities. It is widely accepted that hyaluronan-CD44 interactions are crucial in both malignancy and resistance to therapy, but major challenges for future research in the field are the mechanism of activation of hyaluronan-CD44 signaling in cancer cells, the relative importance of variant forms of CD44 and other hyaluronan receptors, e.g., Rhamm, in different tumor contexts, and the role of stromal versus tumor cell production and turnover of hyaluronan. Despite these caveats, it is clear that hyaluronan-CD44 interactions are an important target for translation into the clinic. Among the approaches that show promise are antibodies and vaccines to specific variants of CD44 that are uniquely expressed at critical stages of progression of a particular cancer, hyaluronidase-mediated reduction of barriers to drug access, and small hyaluronan oligosaccharides that attenuate constitutive hyaluronan-receptor signaling and enhance chemosensitivity. In addition, hyaluronan is being used to tag drugs and delivery vehicles for targeting of anticancer agents to CD44-expressing tumor cells. (Clin Cancer Res 2009;15(24):7462-8)

show abstract

“…It contributes to cells many biological functions, including cell motility 5,6, wound healing 7,8 and signal transduction 7,9. In cancer cases, RHAMM is overexpressed in many solid tumors such as stomach 10, prostate 11, breast 12, colorectal cancers 13 and lung 14. Besides, RHAMM is also the treated target of B-cell chronic lymphocytic leukemia, multiple myeloma and acute myeloid leukemia 15.…”

Section: Introductionmentioning

confidence: 99%

Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors

et al. 2017

View full text Add to dashboard Cite

It remains a substantial challenge to targetedly deliver drug to both primary tumors and metastatic lesions employing a single nanoparticle delivery system. Here aiming at the receptor for hyaluronic acid mediated motility (RHAMM or CD168), a specific receptor for hyaluronic acid (HA), the bioreductive responsive HA nanogels loaded doxorubicin were prepared. The targeting effects of HA nanogels in high RHAMM-expressed cancer cells, primary and metastatic tumors were investigated. It was found that HA nanogels show a strong in vitro and in vivo RHAMM-mediated cellular uptake and drug delivery. The cellular uptake of HA nanogels in high RHAMM-expressed LNCaP and H22 cells was far more than the uptake in low RHAMM-expressed NIH3T3 cells. The IC50 value of drug-loaded HA nanogels against H22 cells was lower than that of free drug. In vivo antitumor activity examinations showed that the HA nanogels not only had significantly superior antitumor efficacy in murine H22 and human LNCaP tumor-bearing mice but also exhibited much deep tumor penetration. The drug delivery of lymph node metastasis by systemically administering HA nanogels demonstrated that the HA nanogels could sufficiently increase drug concentration in metastatic lymph node by RHAMM-HA interaction and inhibit the growth of metastatic lymph node, even completely heal malignant lymph node metastasis. Thus, RHAMM-directed drug delivery is a promising therapy route for treating both primary and metastatic tumors.

show abstract

A Pilot Human Evaluation of a Formulation of Irinotecan and Hyaluronic Acid in 5-Fluorouracil-Refractory Metastatic Colorectal Cancer Patients

Cited by 28 publications

References 86 publications

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Versican induces a pro-metastatic ovarian cancer cell behavior which can be inhibited by small hyaluronan oligosaccharides

Hyaluronan-CD44 Interactions in Cancer: Paradoxes and Possibilities

Redox Responsive Hyaluronic Acid Nanogels for Treating RHAMM (CD168) Over-expressive Cancer, both Primary and Metastatic Tumors

Contact Info

Product

Resources

About