Opiate-Antagonist Reversal of Neurological Deficits –Experimental and Clinical Studies–

Abstract: The proximal left M₁ and the common trunk of A₂ were clipped in 12 adult dogs. Naloxone was injected after placing the clips onto 6 dogs. Neither the systemic blood pressure nor the local cerebral blood flow were influenced by naloxone. In another group of 6 dogs with chronic right hemiplegia, naloxone proved passably effective in improving the hemiplegia. Eight patients with neurological deficits of various etiologies were administered levallorphan. The improvement in motor performance and/or elevation of mental activity was observed more or less in all but 2 of the patients. It was consideredthat the effect of opiate antagonists is based partially on the facilitation of synaptictransmission exaggerated by the arousal response.     

Cumulative effects of lentinan and endocrine therapy on the growth of DMBA-induced mammary tumor in rats

The cumulative effects of Lentinan and endocrine therapy on the growth of DMBA (7, 12-dimethyl benzanthracene)-induced mammary tumors of rats were studied. Multiple injection of Lentinan alone resulted in a slight degree of regression of the tumor growth, when administered to rats bearing mammary tumors of about 1 cm in size. Ovariectomy-adrenalectomy, ovariectomy, and adrenalectomy, which are performed as surgical endocrine therapy, resulted in a more marked regression of the tumor than that produced by Lentinan treatment alone. Furthermore, multiple injection of Lentinan performed on these mammary tumor-bearing rats which had received surgical endocrine therapy 2 weeks previously evoked a marked regression of tumor growth. However, no changes in growth curves and survival rates, compared with those of saline controls were observed, indicating that Lentinan might be a useful agent when combined with surgical endocrine therapy. Concurrent injection of Lentinan resulted in a slight augmentation, although the histamine sensitivity of tumor bearing rats which had previously received surgical endocrine therapy elevated greatly, compared with that of controls. By contrast administration of Tamoxifen, which is used for medical endocrine therapy, resulted in a lesser degree of regression than that observed following surgical endocrine therapy, and was also not greatly affected by Lentinan injection.     

Plant antitumor agents. 29. Synthesis and biological activity of ring D and ring E modified analogues of camptothecin

The total synthesis of the pentacyclic camptothecin analogues 3 and 4 in 11 steps from p-tolualdehyde is described. The overall shape of compound 3 is the same as that of potent, naturally occurring camptothecin (1a). Despite the near spatial identity of 3 and 1b (racemic, (20RS)-camptothecin) from a three-dimensional standpoint, the 9KB and 9PS cytotoxicity assays indicate at least a 40-60-fold decrease in activity of 3 compared to that of 1b, and the isomer 4 was inactive. Similarly, studies of the inhibition of topoisomerase I activity indicated only slight activity for 3 and no activity for 4. It is evident that the pyridone ring D is essential for antitumor activity. Three E ring modified analogues of camptothecin, 2d-f, are described in which the net change is replacement of O by N in ring E. Compared to (20S)-camptothecin (1a) or (20RS)-camptothecin (1b), the ring E modified analogues 2d-f display little or no cytotoxic activity, greatly reduced effect on the inhibition of topoisomerase I, and total loss of life prolongation in the in vivo L-1210 mouse leukemia assay, indicative of the highly restricted structural and electronic requirements of ring E for biological activity in camptothecin.     

Indoles in edible members of the Cruciferae

Antimutagenic fractions from collards yielded indole-3-carboxaldehyde [4] and traces of indole-3-acetonitrile [2]. The compounds had no antimutagenic activity. An analytical procedure for various indoles in plants was developed based on reversed-phase hplc. The indoles studied included the 3-carbinol 1, the acetonitrile 2, the carboxaldehyde 4, the 3-carboxylic acid 5, and the 3-acetic acid 6. Many Cruciferae and non-Cruciferae were analyzed. The latter did not contain measurable quantities of these compounds. In the case of the Cruciferae--with the exception of collards, which consistently indicated the presence of the aldehyde 4--major indole found was the nitrile 2. Although a particularly careful search for the carbinol 1 was conducted, only trace levels were noted. A review of the literature indicates that the content and occurrence of this indole in plants have been heavily overestimated. Because of the low levels found in the Cruciferae, our studies indicate that the role of the compound as a dietary factor may be questionable.     

Plant antimutagenic agents, 3. Coumarins

Several coumarins were isolated from crude plant extracts by means of an antimutagenic assay procedure. These coumarins included psoralen from Psoralea corylifolia and imperatorin and osthol from Selinum monniere. Studies of structure-activity relationships of these and several other available coumarins were carried out with four mutagens. All of the coumarins were nontoxic and in particular showed high activity in the inhibition of the mutagenicity of benzo[a]pyrene.     

Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity

Twenty-two compounds related to camptothecin, a known inhibitor of eukaryotic topoisomerase I, were studied. The following effects on the actions of topoisomerase I were observed and were well correlated among most of the compounds studied: (a) inhibition of the first-order rate of relaxation of supercoiled DNA; (b) conversion of supercoiled DNA to nicked circles; and (c) single-strand cleavage of linear DNA at specific sites. The locations of the stimulated cleavage sites were the same for all of the active derivatives. Stereochemistry and the positions of substituents were found to be crucial for the presence or absence of effects on topoisomerase I, indicating that the compounds interact with an asymmetrical receptor site on the enzyme or enzyme-DNA complex. From the structure-activity relations, the regions of interaction between the camptothecin ring system and the receptor site were inferred. Striking correlations were observed between activity against topoisomerase I and reported activity against murine leukemias, indicating that an action on topoisomerase I is responsible for the antitumor activity of the camptothecins.