Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models

Merriman, Ronald L.; Hertel, Larry W.; Schultz, Richard M.; Houghton, Peter J.; Houghton, Janet A.; Rutherford, Pamela; Tanzer, Lee R.; Boder, George B.; Grindey, Gerald B.

doi:10.1007/bf00194526

Cited by 71 publications

(34 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…administration, respectively. The dose and schedule of gemcitabine were selected based on prior experience with gemcitabine in these in vivo models (36). Panc-1 tumors were measured with calipers twice weekly, and tumor volume was calculated using the following formula: tumor volume (mm 3 ) = [(width) 2 Â length] / 2.…”

Section: Methodsmentioning

confidence: 99%

Selective Tumor Targeting by the Hypoxia-Activated Prodrug AQ4N Blocks Tumor Growth and Metastasis in Preclinical Models of Pancreatic Cancer

Lalani¹,

Alters²,

Wong³

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: The antitumor activities and pharmacokinetics of the hypoxia-activated cytotoxin AQ4N and its metabolites were assessed in several preclinical models of pancreatic cancers. Experimental Design: The cytotoxic effects of AQ4N prodrug and its bioreduced form, AQ4, were tested against multiple human tumor cell lines using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. Nude mice bearing s.c. or orthotopically implanted human BxPC-3 or Panc-1tumor cells were treated with AQ4N. Tumor growth inhibition, time to progression/end point, and liver metastasis were evaluated in treatment versus control groups. Plasma and tumor levels of AQ4N and its metabolites were quantitated by liquid chromatography-tandem mass spectrometry. Results: In contrast to AQ4N, the bioreduced AQ4 metabolite displayed potent cytotoxicity in many human tumor lines, including those derived from human pancreatic adenocarcinomas. Single-agent administration of AQ4N significantly delayed tumor growth, progression, and survival in a manner comparable with gemcitabine in multiple pancreatic tumor models in vivo. Survival increases were accompanied by a reduction in incidence and spread of liver metastasis. Quantitation of AQ4N and its metabolites in tumor-bearing mice showed that the prodrug is rapidly cleared from the circulation by 24 h and neither of the bioreduced metabolites was detected in plasma. In contrast, AQ4N readily penetrated BxPC-3 tumors and the cytotoxic AQ4 metabolite rapidly accumulated in tumor tissues at high levels in a dose-dependent fashion. Conclusion: AQ4N undergoes rapid and selective conversion into the potent antineoplastic metabolite AQ4 in tumors in vivo and provides proof of principle for the use of hypoxia-activated prodrugs in the treatment against pancreatic cancers.

show abstract

Section: Methodsmentioning

confidence: 99%

Selective Tumor Targeting by the Hypoxia-Activated Prodrug AQ4N Blocks Tumor Growth and Metastasis in Preclinical Models of Pancreatic Cancer

Lalani¹,

Alters²,

Wong³

et al. 2007

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…Gemcitabine is a schedule-dependent anticancer agent (23). When dosed orally, LY2334737 is rapidly absorbed intact and shows rate-limited formation of gemcitabine and prolonged gemcitabine exposure (9).…”

Section: Ly2334737 Dose-response Studies In the Hct-116 Xenograft Modelmentioning

confidence: 99%

“…Because gemcitabine is a schedule-dependent anticancer agent, the dose response for LY2334737 efficacy in the HCT-116 xenograft model was evaluated using several schedules (23). Additional efficacy studies were conducted with xenografts derived from established human cell lines or patient tumors.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Pratt

Durland-Busbice

Shepard

et al. 2013

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non-small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response.

show abstract

“…For example, Gemcitabine, the first-line anticancer agent for pancreatic adenocarcinoma, exhibits potent in vitro inhibitory effects on cells derived from the human pancreatic adenocarcinoma line BxPC3. 7) However, its inhibition of xenograft BxPC3 tumors in mice 8) is unimpressive. And in humans, Gemcitabine only prolongs survival, with significant effects confined to improvement of quality of life.…”

mentioning

confidence: 99%

Pericyte-Coverage of Human Tumor Vasculature and Nanoparticle Permeability

Zhang

Nishihara

Kano

2012

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

Nano drug delivery systems (nanoDDS) are a promising strategy for treatment of human tumors. As indicated by our previous work, the extent of pericyte-coverage of tumor vasculature is important to determining nanoDDS efficacy since intratumoral accumulation of nanoDDS is less in tumor models with pericyte-covered vasculature. Here we investigated the clinical relevance of our previous observations in animal models, by determining pericyte coverage using immunohistochemistry of smooth muscle actin (SMA) with CD34: a vascular endothelial marker, in human tumor tissue samples. The investigation revealed that tumor vasculature coverage by pericytes in pancreatic and diffuse-type gastric cancers was significantly greater than in ovarian, colon, and intestinal-type gastric cancers. The latter group of cancers is easier to treat clinically. These observations are consistent with our previous findings in animal models. On the basis of these findings we believe optimization of nanoDDS delivery should be done depend upon a clear understanding of the effects of pericyte vascular coverage.

show abstract

Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models

Cited by 71 publications

References 8 publications

Selective Tumor Targeting by the Hypoxia-Activated Prodrug AQ4N Blocks Tumor Growth and Metastasis in Preclinical Models of Pancreatic Cancer

Selective Tumor Targeting by the Hypoxia-Activated Prodrug AQ4N Blocks Tumor Growth and Metastasis in Preclinical Models of Pancreatic Cancer

Efficacy of Low-Dose Oral Metronomic Dosing of the Prodrug of Gemcitabine, LY2334737, in Human Tumor Xenografts

Pericyte-Coverage of Human Tumor Vasculature and Nanoparticle Permeability

Contact Info

Product

Resources

About