Tumor inhibiting properties of stereoisomeric [1,2-bis(3-hydroxyphenyl) ethylenediamine]dichloroplatinum(II)-complexes, Part II: Biological properties

The activity of stereoisomeric [1,2-bis(3-hydroxyphenyl)ethylenediamine] dichloroplatinum(II)-complexes (1-PtCl2,R,S; 2-PtCl2, R,R/S,S; 3-PtCl2, R,R; 4-PtCl2, S,S) on several tumor models (MDA-MB 231 breast cancer cell line; P 388 leukemia, mouse; L 1210 leukemia, mouse; L 5222 leukemia, rat; Ehrlich ascites tumor, mouse--wildtype; cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.) is described. For comparison the analogous [1,2-bis(4-hydroxyphenyl)ethylendiamine]dichloroplatinum (II)-complexes (5-PtCl2, R, S; 6-PtCl2, R,R/S,S; 7-PtCl2, R,R; 8-PtCl2, S,S) and cisplatin are used. 1-PtCl2 to 4-PtCl2 (OH in 3,3'-positions) show their maximum antitumor effect at lower doses than 5-PtCl2 to 8-PtCl2 (OH in 4,4'-positions). 2-PtCl2 and 6-PtCl2 (R,R/S,S) are more active than 1-PtCl2 and 5-PtCl2 (R,S). 4-PtCl2 and 8-PtCl2 (S,S) are superior to 3-PtCl2 and 7-PtCl2 (R,R). On the L 5222 leukemia 2-PtCl2 (R,R/S,S), 4-PtCl2 (S,S) and 8-PtCl2 (S,S) markedly surpass cisplatin. Strong effects are produced by 2-PtCl2 to 4-PtCl2 on the Ehrlich ascites tumor (wildtype, cisplatin-, etoposide-, cyclophosphamide-, and daunomycin-resistant, resp.). The combination of 4-PtCl2 with cisplatin results in a weakly synergistic effect.     

Investigation of the negative chronotropic action of SK&F 86466 in the pithed normotensive rat

SK&F 86466, 6-chloro-3-methyl-2,3,4,5-tetrahydro-1-H-3-benzazepine, is a potent and selective antagonist of the α₂-adrenoceptor in vitro. This compound produced a small pressor response accompanied by a marked bradycardia when administered i.v. to the pithed normotensive rat. The pressor response was not affected by reserpine treatment, pretreatment with α- or β-adrenoceptor antagonists, atropine, or hexamethonium. The bradycardia was markedly reduced by bilateral vagotomy and pretreatment with atropine and attenuated by hexamethonium. The negative chronotropic action of SK&F 86466 was abolished by a combination of vagotomy and atropine. Mediation of the bradycardia by a baroreceptor reflex was ruled out by the observations that a lack of change in heart rate was associated with the vasopressor response to phenylephrine in the pithed rat pretreated with propranolol. It is concluded that the negative chronotropic action of SK&F 86466 in the pithed rat is mediated indirectly by activation of the cholinergic innervation of the heart.     

Role of cytochrome P450IIIA4 in the metabolism of the pyrrolizidine alkaloid senecionine in human liver

Studies were carried out to investigate the metabolism of senecionine by human liver microsomes and the role of human cytochrome P450IIIA4 in this process. Human liver microsomes metabolized senecionine to two major products, (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP) and senecionine N-oxide. The rates of product formation (DHP and senecionine N-oxide) varied widely with the microsomal samples tested. There was a 30-fold difference in DHP formation and a 25-fold difference in N-oxidation between the poorest metabolizer and the highest metabolizer of senecionine. The conversion of senecionine to DHP and senecionine N-oxide in human liver microsomes was markedly inhibited by the mechanism-based inactivators of P450IIIA4, gestodene and triacetyloleandomycin. Anti-P450IIIA4 IgG, at a concentration of 1 mg/nmol of P450, was found to inhibit completely the formation of DHP and senecionine N-oxide in human liver microsomes (HL101) having low activity toward senecionine. At 5 mg IgG/nmol P450, anti-P450IIIA4 inhibited 90 and 84% respectively of the formation of DHP and senecionine N-oxide in liver microsomes (HL110) with the highest activity toward senecionine. The formation of DHP or senecionine N-oxide was highly correlated with the amount of P450IIIA4 measured in the microsomes using polyclonal anti-P450IIIA4 IgG. The rate of DHP production also had a strong correlation with the rate of senecionine N-oxide formation (r = 0.999) and with the rate of nifedipine oxidation (r = 0.998). Our present studies provide evidence that P450IIIA4 is the major enzyme catalyzing the bioactivation (DHP formation) and detoxication (senecionine N-oxide formation) of senecionine in human liver.     

Apoptosis: understanding the new molecular pathway.

Advances in science have increased the knowledge of how cells die in the body (apoptosis). A basic understanding of this process can improve nurses' ability to review new scientific literature and enable them to provide safer bedside care.