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Biomedical subjects

A M Creighton

Publications and source records attributed to A M Creighton.

27 records · Page 2Linked to original sources
PubMed1982

Metal binding by pharmaceuticals. Part 2. Interactions of Ca(II), Cu(II), Fe(II), Mg(II), Mn(II) and Zn(II) with the intracellular hydrolysis products of the antitumour agent ICRF 159 and its inactive homologue ICRF 192.

Formation constants for the calcium(II), copper(II), iron(II), magnesium(II), manganese(II) and zinc(II) complexes of dl-NN'-dicarboxamidomethyl-NN'-dicarboxymethyl-1,2-diaminopropane (ICRF 198) and the 1,2-diamino-butane homologue (ICRF 226) have been measured potentiometrically at 37 degrees C and I=150 mmol dm-3 [NaCl]. The constants are used in computer simulation models to assess the relative avidity of these compounds for biologically essential metal ions in vivo. It is shown that the agents interact similarly with all of the ions studied except those of zinc(II), which are particularly strongly chelated by the hydrolysis product of ICRF 192. This effect could be responsible for the difference in cytotoxicity exhibited by the antitumour agent ICRF 159 (Razoxane) and its inactive homologue ICRF 192. However, the mechanism through which this might occur remains unclear.

Antineoplastic Agents↗
PubMed1982

Inheritance of cellular resistance to the antitumor agent ICRF 159 in somatic cell hybrids.

Two independently derived sublines of Syrian hamster BHK 21 S cells that demonstrate resistance to the antitumor agent ICRF 159 (NSC-129943) were fused to sensitive cells in both intraspecific and interspecific crosses, and the responses of the resultant hybrids to the drug were determined. In intraspecific hybrids from crosses involving either of the sublines, resistance to ICRF 159 was expressed codominantly ith the hybrid response being halfway between the parental responses. In interspecific hybrids from crosses with sensitive mouse cells, resistance was also expressed but to a lesser extent than in the intraspecific hybrids. However, subsequent passaging of an interspecific hybrid resulted in an increase in the degree of resistance, which appeared to be accompanied by a loss of telocentric mouse chromosomes. The results suggested that resistance in these lines was due to an alteration in the cellular target involved in the response to ICRF 159.

Animals↗
PubMed1981

ICRF 159-induced cell-cycle perturbation in vitro: its relationship to inhibition of colony-forming ability.

The effects of single doses of ICRF 159 (Razoxane) on the cell-cycle kinetics of lines of BKH 21S cells in vitro were studied by means of flow micro-fluorometry (FMF). A characteristic accumulation of cells in the 4n DNA region after 6 h in the presence of ICRF 159 was evident in cells which were sensitive to the cytotoxic effects of the agents, as judged by colony-forming assays. The subsequent accumulation of 8n cells as the major population within 24 h indicates that this 6 h effect is associated with the induction of tetraploidy through abnormal mitosis, rather than reflecting a G2 block of potential value in combination therapy. In ICRF 159-resistant sublines, the cell-cycle distributions were similarly affected, but only the doses of the drug high enough to reduce their surviving fraction. Somatic cell hybrids from crosses between sensitive and resistant cells demonstrated intermediate responses in ICRF 159, both in terms of cell-cycle kinetics and impairment of reproductive integrity. These data suggest a relationship between the 2 manifestations of the cellular action of ICRF 159, and also a possible predictive role for FMF in the assessment of response to this particular agent.

Animals↗