Low-Dose Metronomic Oral Dosing of a Prodrug of Gemcitabine (LY2334737) Causes Antitumor Effects in the Absence of Inhibition of Systemic Vasculogenesis

Abstract

Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low minimally toxic doses with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials, and is currently undergoing phase III trial evaluation. It is thought to cause anti-tumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow derived cells, including circulating endothelial progenitor cells (CEPs). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, anti angiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T cell responses, or by direct anti-tumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 (LY) in non tumor-bearing mice, and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6mg/kg/day) the schedules tested were devoid of toxicity and caused anti-tumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly metronomic LY administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts; and this effect coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant anti-tumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.

Inhibitory effect of emodin on migration, invasion and metastasis of human breast cancer MDA-MB-231 cells in vitro and in vivo

“…Although these natural products have been shown to be highly effective in clinical trials (29), some drugs such as vinblastine and paclitaxel can produce drug resistance (30), and other drugs such as vincristine, produce a strong cytotoxic effect (31). It has also been reported that treatment with topotecan, a water-soluble derivative of camptothecin, caused immunologic suppression in breast cancer (LM2-4) xenografts (32). Therefore, the identification of safer and more effective drugs from natural medical plants for breast cancer metastasis is crucial.…”

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

“…For example, LY2334737, an orally bioavailable prodrug of gemcitabine, exhibited antitumor effects in preclinical models of ovarian and breast cancer when administered in metronomic doses. 35 In the current study, the design of GnRH-gemcitabine conjugates was based on improving the therapeutic potential of gemcitabine as follows: 1) Reduction of gemcitabine's metabolic inactivation. It has been shown that gemcitabine prodrugs can be designed specifically to affect its interaction with cytidine deaminase, the enzyme responsible for gemcitabine's poor pharmacokinetic properties.…”

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

“…When metronomically dosed orally once a day for 14 days in the human colon HCT-116 xenograft model, LY2334737 showed excellent antitumor activity that is equivalent to standard high doses of gemcitabine.HCl typically administered intraperitoneally (9). Orthotopic models of human metastatic breast LM2-and ovarian SK-OV-3 cancers also responded well to LY2334737 treatment (16).…”

“…"Metronomic dosing" refers to administration of chemotherapy at frequent intervals (e.g., daily) with low, minimally toxic doses (13). In contrast to intravenous delivery of maximally tolerated doses of chemotherapeutic agents, advantages include: (i) direct, continual tumor growth inhibition and (ii) an indirect effect through inhibition of angiogenesis and vasculogenesis (13)(14)(15) or, as shown for LY2334737, increased tumor blood flow thereby potentially enhancing drug delivery (16). When metronomically dosed orally once a day for 14 days in the human colon HCT-116 xenograft model, LY2334737 showed excellent antitumor activity that is equivalent to standard high doses of gemcitabine.HCl typically administered intraperitoneally (9).…”