gambogic-acid and Body-Weight

DDO-6101, a natural-product-like caged xanthone discovered previously in our laboratory based on the pharmacophoric scaffold of Garcinia natural product gambogic acid (GA), shows potent cytotoxicity in vitro but poor efficacy in vivo due to its poor druglike properties. In order to improve the druglike properties and in vivo cytotoxic potency, a novel series of 19 prenyl group-modified derivatives of DDO-6101 was synthesized and evaluated for their in vitro antitumor activity and druglike properties. The SAR and SPR information of these compounds was also obtained. In the light of the in vitro antitumor activity and druglike properties such as aqueous solubility and permeability, compound 6f (named as DDO-6306) was advanced into in vivo efficacy experiment. The results showed that DDO-6306 is more potent than DDO-6101 in vivo and is a promising antitumor candidate for further evaluation.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biological Products; Body Weight; Cell Line, Tumor; Cell Membrane Permeability; Cell Proliferation; Drug Screening Assays, Antitumor; Garcinia; Humans; Mice; Structure-Activity Relationship; Transplantation, Heterologous; Xanthones

In this article, the general pharmacological toxicity of gambogic acid (GA), a new anticancer agent, on the dog cardiovascular and respiratory system and the mouse central nervous system (CNS) were observed. The developmental toxicity and analgesic activities of GA were also investigated in rats and mice. Results showed that GA did not cause any toxic symptoms on blood pressure (i.e., mean arterial pressure), heart rate (HR), and respiratory frequency. However, a high dose of GA showed slight side effects on the mouse CNS. Further, evidence of maternal and developmental toxicity was observed in a dose-dependent manner. The maternal body-weight gain, as well as the birth weights and live birth index, were decreased significantly in the treatment groups. The inhibitory effects of GA on fetal skeletal development were also found. No obvious effects of GA on external alterations and visceral alterations were shown. In the analgesic experiments, GA showed significant analgesic activity in the acetic-acid-induced writhing study in a dose-dependent manner. This mechanism might be related to its anti-inflammation properties.

Topics: Abnormalities, Drug-Induced; Analgesics; Animals; Antineoplastic Agents; Body Weight; Dogs; Eating; Female; Fetal Development; Mice; Organ Size; Xanthones

To study the chronic toxicity of gambogic acid (GA), the major active ingredient of gamboges, a brownish to orange resin extracted from the Garcinia hanburyi (family Guttiferae) in Southeast Asia, using Sprague-Dawley rat as an animal model and provide further theoretical support for clinical applications of this promising natural anticancer agent.. GA was administered orally at dosages of 120, 60 and 30 mg/kg once every other day for a total of 13 weeks. Then we carried out the chronic toxicity studies including general body parameters, hematological, serum biochemistry, histopathological, and viscera examination.. The results from the studies demonstrated that rats treated with high dose (120 mg/kg) of GA for a long time can lead to the damage on the kidney and liver. An innocuous dose was established to be 60 mg/kg after administration to rats for a total of 13 weeks at a frequency of one administration every other day. This dose was approximately 18.0 (body weight) or 9.6 (body surface area) times higher then that of the dose (200mg/60 kg, every other day) used for human trials.. The studies demonstrated that the toxicity targets in the rats were the kidney and liver. These results provide further theoretical support for clinical applications of this promising natural anticancer agent.

Topics: Animals; Antineoplastic Agents, Phytogenic; Behavior, Animal; Blood Cell Count; Body Weight; Female; Garcinia; Kidney; Liver; Liver Function Tests; Male; Myocardium; Organ Size; Rats; Rats, Sprague-Dawley; Xanthones