Cynthia L. Nichols

Elevation of acetylcholine levels in striatum of rat brain by LY163502, trans−(−)−5,5a,6,7,8,9a,10-octahydro-6-propylpyrimido〈4,5−g〉quinolin-2- amine dihydrochloride, a potent and stereospecific dopamine (D2) agonist

LY163502, a partial ergoline and a trans-levorotatory enantiomer, does not stimulate adenylate cyclase in striatal membranes but inhibits 50% binding of 3H-apomorphine, 3H-pergolide and 3H-spiperone at 10, 13 and 151 nM (IC50), respectively. The racemic mixture (LY137157) is less effective, with 3, 2.7 and 1.4 times higher IC50 values, respectively, whereas the dextrorotatory isomer (LY175877) is inactive. LY163502 inhibits binding of 3H-clonidine with an IC50 value of 2600 nM, but not the binding of 3H-WB4101, 3H-dihydroalprenolol, 3H-serotonin, 3H-quinuclidinyl benzilate and 3H-pyramilamine or the uptake of serotonin, norepinephrine or dopamine, suggesting selective affinity toward dopamine receptors in vitro. Both LY163502 and LY137157 elevate striatal acetylcholine (Ach) levels. The elevation of Ach levels by LY163502 is reversed by dopamine antagonists haloperidol, cis-flupenthixol and metoclopramide. Therefore, the levorotatory enantiomer exhibits pharmacology of a D2 type of dopamine agonist.

In vivo efficacy of monoclonal antibody-drug conjugates of three different subisotypes which bind the human tumor-associated antigen defined by the KS1/4 monoclonal antibody.

SummaryA panel of three hybridomas has been isolated each of which secretes a single species of monoclonal antibody (MoAb) directed against the KS1/4 tumor-associated antigen originally described by Varki et al. (Cancer Res 44:681, 1984). These MoAbs were designated L1-(IgG2b), L2-(IgG1), and L4-(IgG2a) KS. Binding specificity, immunoprecipitation, and competitive binding analyses indicated that these MoAbs each recognize the same epitope of the KS1/4 antigen. The immunoprecipitation studies indicated that the MoAbs recognized a major antigenic component of 42 kDa and a minor component of 35 kDa. The L-KS antibodies were evaluated as MoAb-drug conjugates against a variety of human tumor targets grown in vivo as nude mouse xenografts. The MoAb-drug conjugates were constructed using protein-A-purified MoAbs conjugated to 4-desacetyl-vinblastine-3-carboxhydrazide. Efficacy was determined using various dosing protocols on 2–14 day established tumors of lung, pharynx, colon, and skin origin. Control experiments included the use of dual-flank antigen-positive and negative tumors, free MoAbs, free drug, and mixtures of MoAbs and drug. These studies indicated that significant tumor growth supression and actual tumor regression could be achieved by the MoAb — vinca conjugates and that this activity was antigen-mediated. The drug conjugates were more efficacious than free drug or free MoAbs administered either singly or in combination with each other.