Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts

Our plain-English summary of Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts, by S.E. Pratt, S. Durland-Busbice, R.L. Shepard, et al (Molecular Cancer Therapeutics, 2013).

The study

• Authors: S.E. Pratt, S. Durland-Busbice, R.L. Shepard, G.P. Donoho, J.J. Starling, E.R. Wickremsinhe, E.J. Perkins, A.H. Dantzig
• Journal: Molecular Cancer Therapeutics
• Published: 2013;12(4):481-90
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

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.

In plain English

This was a laboratory study in mice of LY2334737, an oral prodrug of the chemotherapy drug gemcitabine. A prodrug is a drug the body converts into another drug. The study did not examine asbestos exposure. Mice carrying human tumors, grown from cell lines or patient tumors, were given frequent low oral doses, which the authors call metronomic dosing. In HCT-116 colon tumors, three dosing schedules significantly slowed tumor growth at some doses, and the highest doses on two schedules were toxic. In seven mice per group bearing a patient-derived pleural mesothelioma tumor, PXF 1118, oral LY2334737 (6.0 mg/kg daily for 21 days) and intravenous gemcitabine.HCl (240 mg/kg weekly for 3 weeks) both significantly inhibited tumor growth, and the two did not significantly differ. Responses in three lung cancer tumors varied. In LXFE 1422, the prodrug's effect was not statistically significant versus controls; in LXFE 397, it exceeded gemcitabine's after day 21. In three colon tumor models, LY2334737 combined with capecitabine inhibited growth more than either drug alone. The authors concluded that this dosing was efficacious, well tolerated and easily combined with capecitabine.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: mice carrying human tumor xenografts, with supporting cell-culture (in vitro) tests
• Who was studied: Mice bearing human tumors. The tumors were the HCT-116 and HT-29 colon cell lines and patient-derived tumors: pleural mesothelioma PXF 1118, non-small cell lung cancer LXFE 937, LXFE 1422 and LXFE 397, and colon CXF 676. Groups had 7 to 10 mice. Patient-tumor and HT-29 studies used NMRI nu/nu mice at Oncotest GmbH.
• Exposure: Drug treatments, not asbestos. Oral LY2334737 was given on several low-dose schedules. In the lung and mesothelioma studies, the comparison was intravenous gemcitabine.HCl (240 mg/kg, or 160 mg/kg in one study, once a week for 3 weeks). Colon studies also tested oral capecitabine alone and combined with LY2334737.
• Main results:
  • HCT-116 colon tumors, once-daily dosing for 14 doses: 7.55 mg/kg LY2334737 gave 67% maximal tumor growth inhibition on day 26. This was as efficacious as gemcitabine.HCl 160 mg/kg given intraperitoneally every 3 days for 4 doses.
  • HCT-116 colon tumors, every-other-day dosing for 7 doses: the highest dose, 26 mg/kg, was toxic and the group was stopped early. Maximum inhibition was 48% in the 13 mg/kg group.
  • HCT-116 colon tumors, alternate-week schedule: the 10.5 mg/kg dose was toxic and stopped early. Maximum inhibition was 64% in the 6 mg/kg group.
  • Pleural mesothelioma PXF 1118 and squamous lung tumor LXFE 937: both LY2334737 and gemcitabine significantly inhibited tumor growth. Efficacy did not significantly differ between the two drugs.
  • Lung tumor LXFE 1422: LY2334737 was not significantly different from vehicle (p greater than 0.05), while gemcitabine.HCl showed strong antitumor activity.
  • Lung tumor LXFE 397: both drugs gave about 65% growth inhibition during the 21-day treatment. After day 21, inhibition was significantly greater with LY2334737 than with gemcitabine.HCl. This tumor had higher ENT1 and RRM1 expression; LXFE 937 had higher CES2 expression.
  • Tolerability across the 4 lung and mesothelioma studies: weight loss was less than 6% and 2 deaths occurred. One was in the LY2334737-treated LXFE 937 group and one in a vehicle-treated LXFE 1422 mouse.
  • HCT-116 colon tumors: LY2334737 (4 mg/kg) plus capecitabine (175 mg/kg) gave significantly greater inhibition than either drug alone. Maximum inhibition was 77% with the combination, compared with 50% to 55% for each drug alone.
  • HT-29 colon tumors: maximum inhibition was 89% for LY2334737, 68% for capecitabine and 93% for the combination.
  • Patient-derived colon tumor CXF 676: maximum inhibition was 51% for LY2334737, 60% for capecitabine and 78% for the combination.
• The authors' conclusion: The authors concluded that frequent low-dose oral LY2334737 was efficacious, well tolerated and easily combined with capecitabine for improved efficacy. They also suggested that elevated CES2 or ENT1 expression in a tumor may enhance its response.

Topics

Medical terms in this study, explained in our Lexicon: Gemcitabine, Mesothelioma, Non-Small Cell Lung Cancer, Capecitabine, Fluorouracil (5-FU).

Related studies

• Pilot Study to Predict Pharmacokinetics of a Therapeutic Gemcitabine Dose From a Microdose — M. Van Nuland, H. Rosing, et al. (2020)
• Highly efficient tumor transduction and antitumor efficacy in experimental human malignant mesothelioma using replicating gibbon ape leukemia virus — S. Kubo, M. Takagi-Kimura, et al. (2013)
• A specific inhibitor of lactate dehydrogenase overcame the resistance toward gemcitabine in hypoxic mesothelioma cells, and modulated the expression of the human equilibrative transporter-1 — E. Giovannetti, L.G. Leon, et al. (2016)
• Design of pH responsive clickable prodrugs applied to histone deacetylase inhibitors: a new strategy for anticancer therapy — R. Delatouche, I. Denis, et al. (2013)
• A dose-finding study of gemcitabine and vinorelbine in advanced previously treated malignancies — J.P. Delord, E. Raymond, et al. (2000)
• Microspheres targeted with a mesothelin antibody and loaded with doxorubicin reduce tumor volume of human mesotheliomas in xenografts — S.L. Macura, J.L. Steinbacher, et al. (2013)

Browse more research in Molecular Cancer Therapeutics, or return to medical research.