Interaction of synthetic opioid metenkephalin peptide analogs, lilly 127623 and FK 33-824 with indole hallucinogens: Antagonism of N,N-dimethyltryptamine- and LSD-induced disruption of food-rewarded bar pressing behavior in the rat

The selected opioid metenkephalin synthetic peptide analogs Lilly (LY) 127623 and FK 33-824 were tested for behavioral dose effects and potential interaction with N,N-dimethyltryptamine (DMT) and lysergic acid diethylamide-25 (LSD) in adult male Holtzman rats trained on a positive reinforcement fixed-ratio 4 (FR-4) behavioral bar pressing schedule, i.e., a reward of 0.01 ml sugar-sweetened evaporated milk was earned on every fourth bar press. DMT (3.2 mg/kg) and LSD (0.1 mg/kg), administered IP following a 0.9% NaCl 15–20-min control pretreatment, disrupted established food-rewarded FR-4 bar pressing in a consistent and reproducible manner. Animals pretreated IP with predetermined behaviorally noneffective doses of LY 127623 (0.01–0.32 mg/kg) and FK 33-824 (0.001–0.01 mg/kg) 15–20 min prior to receiving DMT demonstrated significant antagonism to DMT-induced disruption of FR-4 bar pressing, while doses of 0.10–0.32 mg/kg LY 127623 and 0.00032–0.0032 mg/kg FK 33-824 significantly antagonized LSD-induced behavioral effects.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46430/1/213_2004_Article_BF00432112.pd

Combination of oncolytic adenoviral therapy with chemotherapy for enhanced breast cancer cell killing.

Abstract Abstract #2129 Oncolytic adenoviruses are emerging agents for treatment of cancer by tumor-restricted virus replication, cell lysis and virus spread. A promising oncolytic adenovirus agent, known as Ad5-24-RGD, harbors a 24-bp deletion in the E1A gene that abrogates the binding of E1A to the retinoblastoma tumor suppressor (Rb) and presents enhanced infectivity of primary cancer cells due to insertion of an Arg-Gly-Asp (RGD) motif into the fiber knob. Thus, Ad5-24-RGD has improved cancer cell infection efficiency due to expanded tropism toward alpha-v integrins. It also replicates selectively in cancer cells with Rb/p16 mutations. As with conventional therapy regimes, oncolytic virotherapy, by itself, has limited success in complete tumor eradication in both preclinical animal models and clinical studies. Combination of anticancer agents with different modes of action remains a mainstay in cancer treatment. We undertook one approach towards this end by combining oncolytic adenoviral therapy with chemotherapy. In this study, we investigated a combination treatment of breast cancer cells with Ad5-4-RGD and Docetaxel, a microtubule-stabilizing taxane that is being used in the clinic for the treatment of breast and prostate cancers and small cell carcinoma of the lung. Our results indicate a synergistic effect between Docetaxel and Ad5-24-RGD in breast cancer cell killing at a lower dose than either agent alone. These results suggest that viral replication was not inhibited by this chemotherapy treatment and that chemotherapy could reduce the amount of viral particles needed to help eradicate the tumor. Administration of lower viral loads would simultaneously improve safety and decrease immunogenicity of the vector. Likewise lower doses of chemotherapy agents would decrease toxicity and side effects. The inclusion of oncolytic adenoviruses into multimodal cancer treatment together with chemotherapy has a potential to become powerful therapeutic regimen. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2129.</jats:p