Potent Cytostatic Agents Research Articles

Prevention of cardiac damage induced by formyl-leurosine, a potent cytostatic agent, by radio-detoxified endotoxin (Tolerin) in dogs.

Radio-detoxified endotoxin (Tolerin), produced by 60Co-gamma irradiation of Escherichia coli 089 endotoxin, can protect dogs against the acute cardiotoxic side-effects of formyl-leurosine, a semi-synthetic Vinca derivative with promising antineoplastic potency. Formyl-leurosine induces a rapid decrease in arterial blood pressure and diminishes the contractile force of the myocardium in the anaesthetized dog. These responses indicate a direct pharmacologic relaxant effect of the drug on the heart and vasculature smooth muscle. The early cardiovascular depression is of short duration and is unaffected by Tolerin. Tolerin can prevent, however, the secondary, more dangerous phase of circulatory depression that is associated with the severe cardiotoxic manifestations of the drug, as demonstrated by hemodynamic and morphologic (light and electronmicroscopic) patterns.

Clavines: New antibiotics with cytostatic activity

The cytostatic potentials of ten ergolines were determined in the L5178y mouse lymphoma cell system; six of them belong to the clavines (agroclavine, 1-propyl-agroclavine, 1-propyl-festuclavine, 1-allyl-festuclavine, 6-cyano-6-nor-festuclavine and 1-hydroxymethyl-festuclavine) and four to the lysergic acid derivatives (methylergometrine, lysergic acid amide, isolysergic acid amide and lysergic acid diethylamide). It is shown that agroclavine (ED 50: 3.9 μM), 1-propyl-agroclavine (3.5 μM), 1-propylfestuclavine (4.3 μM) and 1-allyl-festuclavine (4.3 μM) are potent cytostatic agents. Up to 2 × ED 50 concentration the inhibitory effect was completely reversible. Incorporation studies suggested that the compounds inhibit DNA synthesis; this assumption was also supported by the findings which revealed that after incubation with these clavines, the cells showed slight ‘unbalanced growth’. 6-Cyano-6-norfestuclavine was less inhibitory (ED 50 11.8 μM). 1-Hydroxymethyl-festuclavine and all lysergic acid derivatives tested were without any detectable activity.

Stereochemistry of activated cyclophosphamide antitumor drugs: Molecular structure of 4-hydroperoxycyclophosphamide

The crystal and molecular structure of 4-hydroperoxycyclophosphamide, an active cytostatic agent closely related to an active metabolite of the antitumor drug cyclophosphamide, has been determined by X-ray crystallography. The configuration at the phosphorus atom is axial phosphoryl oxygen and equatorial dialkylamino group. The peroxide group attached to C 4 is axial and is thus cis to the phosphoryl oxygen. This same stereochemistry will occur for synthetic 4-hydroxycyclophosphamide, an equally potent cytostatic agent, and is likely for 4-hydroxycyclophosphamide produced by in vivo activation of cyclophosphamide.