Antitumor Effects and Acute Oral Toxicity Studies of a Plant Extract Mixture Containing <i>Rhus verniciflua</i> and Some Other Herbs

Abstract

A novel antitumor agent was developed from six kinds of herbs containing Rhus verniciflua (Rv-PEM01). The components were traditionally established for each formula for traditional medicine. The formula was designed to affect antitumor effect as well as maintain host immune functions. First, we investigated the antiproliferative activities of Rv-PEM01 on human and canine tumor cell lines in vitro, and on antitumor effects using BALB/cAJcl-nu/nu mice in vivo. Acute oral toxicity of Rv-PEM01 was also investigated in vivo in ddY mice. Rv-PEM01 exhibited antiproliferative activities against PC-3 (IC50: 0.328 ± 0.081 mg/ml), A549 (IC50: 0.520 ± 0.070 mg/ml), D-17 (IC50: 0.124 ± 0.037 mg/ml) and MRC-5 (IC50: 0.505 ± 0.058 mg/ml) cells. Luteolin 7-β-D-glucopyranoside and apigenin 7-β-D-glucopyranoside were identified as the main active compounds in Rv-PEM01 by HPLC analysis. The single dose toxicity study of Rv-PEM01 did not result in any deaths or abnormalities in daily behavior, body weight gain, or anatomical observations at necropsy. Thus, so we could not calculate the 50% lethal dose (LD50) in mice, but it would be higher than 5.0 g/kg. Treatment with Rv-PEM01 at a dose of 2.5 g/kg tended to show antitumor activities on mice bearing Colon26 tumors compared with the control group. It was concluded that the formula was a safe * Corresponding author. W. Hiruma et al. 40 antitumor agent with no side effects on mouse physiological function as judged by survival and organ weight.

Clinical Effects of a Plant Extract Mixture Containing <i>Rhus verniciflua</i> and Other Herbs in Tumor Bearing Dogs

“…Although this dosage scheme met these criteria, and Rv-PEM01 was well tolerated at these dosages, the dosages used were significantly less than what would be needed to achieve blood concentrations of the active metabolites equivalent to their in vitro IC 50 's. In previous in vivo studies, single oral doses of 5.0 g/kg Rv-PEM01 produced no evidence of acute toxicity in ddY mice, based on clinical observation, body weight change, and organ weights and chronic dosing at a dosage of 2.5 g/kg daily for 28 days was similarly well tolerated [12]. Based on the excellent tolerability of Rv-PEM01 in tumor bearing dogs found in this study, the lack of apparent toxicity in mice when given Rv-PEM01 at much higher doses, and the concentrations of active compounds needed to produce antitumor activity in vitro, further studies of Rv-PEM01 at higher dosages in tumor bearing dogs are recommended.…”

“…Although no evidence of tumor regression was documented in any of the 12 dogs treated, this study was not designed as an efficacy trial, and a potential role for Rv-PEM01 as a complementary or alternative therapy for cancer treatment, or a role in chemoprevention, remains to be explored. Dosages of Rv-PEM01 evaluated here are significantly less than what is needed to produce antiproliferative effects in vitro [11] [12] suggesting that further studies are warranted in dogs at significantly higher dosage levels.…”

“…The branches and sap from R. verniciflua contain active compounds such as urushiol, fustin, querce tin, butein and sulfuretin; the antioxidant [15] [16], antitumorigenic [17] and cytotoxic [18] effects of these compounds have been reported. The antiproliferative activity of Rv-PEM01 has been demonstrated in human, mouse, and canine cell lines [11] [12]. Notably, D17, the one canine cell line that has been tested, is the most sensitive cell line tested to date [12].…”

“…The antiproliferative activity of Rv-PEM01 has been demonstrated in human, mouse, and canine cell lines [11] [12]. Notably, D17, the one canine cell line that has been tested, is the most sensitive cell line tested to date [12]. The objective of this study was to demonstrate that Rv-PEM01 is safe and well tolerated in dogs with spontaneously occurring tumors.…”

“…In our previous reports, we showed the anti-proliferative activities of a plant extract mixture from six kinds of herbs including R. verniciflua (Rv-PEM01) in vitro. Rv-PEM01 had an inhibitory effect on the proliferation of human, mouse and canine tumor cell lines [11] [12]. Based on these encouraging in vitro results, we conducted a clinical study of Rv-PEM01 in dogs with spontaneously occurring cancers to determine the safety and tolerability of Rv-PEM01 in this population and to document evidence of antitumor activity.…”