L-malate reverses oxidative stress and antioxidative defenses in liver and heart of aged rats.

The intracellular levels of antioxidant and free radical scavenging enzymes are gradually altered during the aging process. An age-dependent increase of oxidative stress occurring throughout the lifetime is hypothesized to be the major cause of aging. The current study examined the effects of L-malate on oxidative stress and antioxidative defenses in the liver and heart of aged rats. Sprague-Dawley male rats were randomly divided into four groups, each group consisting of 6 animals. Group Ia and Group IIa were young and aged control rats. Group Ib and Group IIb were young and aged rats treated with L-malate (210 mg/kg body weight per day). L-malate was orally administrated via intragastric canula for 30 days, then the rats were sacrificed and the liver and heart were removed to determine the oxidant production, lipid peroxidation and antioxidative defenses of young and aged rats. Dietary L-malate reduced the accumulation of reactive oxygen species (ROS) and significantly decreased the level of lipid peroxidation in the liver and heart of the aged rats. Accordingly, L-malate was found to enhance the antioxidative defense system with an increased activity of antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) and increased glutathione (GSH) levels in the liver of aged rats, a phenomenon not observed in the heart of aged rats. Our data indicate that oxidative stress was reversed and the antioxidative defense system was strengthened by dietary supplementation with L-malate.

Effectiveness of water soluble poly(L-glutamic acid)-camptothecin conjugate against resistant human lung cancer xenografted in nude mice.

A camptothecin (CPT) formulation that can be easily administered, is less toxic, and has greater antitumor effect is needed. In this study, a water-soluble CPT derivative was obtained by direct coupling of CPT to poly(L-glutamic acid) (PG) through the C20(S)-hydroxyl group. CPT was released from the resulting conjugate, PG-CPT, in phosphate-buffered saline with a zero-order kinetics in the initial 50 days. The release rates were 0.623% per day, 1.081% per day, and 1.396% per day at pH 5.3, 7.4, and 9.0, respectively. In vitro, PG-CPT was less potent in inhibiting cell growth than was free CPT in all human tumor cell lines tested. However, PG-CPT showed better antitumor activity and tolerability than did CPT in vivo. When H322 human lung tumor cells were inoculated subcutaneously in nude mice, PG-CPT delayed the growth of these well-established tumors with an absolute growth delay of 32 days when given as 4 doses with 4-day intervals between injections at an equivalent CPT dose of 40 mg/kg. When H322 cells were inoculated intratracheally in nude mice, 5 doses of intravenous injection of PG-CPT at an equivalent CPT dose of 10 mg/kg on days 4, 8, 12, 16, and 20 after inoculation significantly prolonged the median survival of treated mice, averaging 1.8-fold that of untreated mice (p=0.01). Increasing the dose of PG-CPT to an equivalent CPT dose of 40 mg/kg per injection administered in 4 doses on days 4, 8, 12, and 16 prolonged the median survival of treated mice by 4-fold (p=0.0008). Significantly, mice with intratracheally inoculated H322 tumors were resistant to both CPT and cisplatin treatments. These studies demonstrated that PG may be used as an effective solubilizing carrier for CPT and that PG-CPT may have potential application in the treatment of lung cancer.