The activity of three iron chelators, methyl [2'-(2-hydroxyphenyl)-2'-thiazoline-4'-carboxylate] (MTL); 2'-(2-hydroxyphenyl)-2'-thiazoline-4'-carboxylic acid (TFAL); and 2-hydroxyphenyl-imido-ethyl-ether (Imidate), regarding antiproliferative, cytocidal, and cell-cycle effects are reported and compared with hydroxyurea (HU). In vitro, against L1210 and P388 murine neoplasms, MTL and TFAL displayed substantially greater antiproliferative activity than HU, although Imidate displayed no appreciable activity. MTL also induced a statistically more complete G1/S cell-boundary block than did HU at equimolar concentrations (100 microM). The IC50 values produced by MTL and TFAL were low enough (less than or equal to 20 microM) to warrant further testing of these chelators as potential antineoplastic agents.

No abstract

A study of the circadian rhythm in the mitotic index (MI) of the corneal epithelium was completed in non-tumor-bearing mice and in mice bearing the Ehrlich ascites carcinoma (EAC). All mice were standardized to a light-dark cycle with 12 hours of light from 0600 to 1800 CST alternating with 12 hours of darkness from 1800 to 0600 CST. Treatments included injection with saline (SAL) or hydroxyurea (HU) at different circadian times. This investigation demonstrated that: (1) Data from untouched animals cannot serve as proper controls because treatment with SAL altered the level of the MI, but only during the diurnal, not the nocturnal, phase of the circadian cycle; (2) the presence of the EAC depressed the level of the MI, but this inhibition was only detected during the diurnal period; (3) treatment with 500 mg/kg HU injected at 0500 caused more perturbation in this rhythm than did treatment with 500 mg/kg HU at 1700; (4) when 500 mg/kg HU was given at 2000 and 0100 and 0500, the perturbation of the rhythm was greater than when 500 mg/kg HU was given at 0900 and 1400 and 1700; (5) when 3000 mg/kg HU was given at 1700 and compared to 500 mg/kg HU at 1700, little difference in the overall circadian profiles of these rhythms was observed, indicating that the circadian control mechanisms operating on the MI exerted a greater influence than did a dosage change from 500 to 3000 mg/kg HU; and (6) a comparison of the practice of plotting experimental and control data as "hours after treatment" versus using a "time of day" plot for the same data demonstrated that the "hours after treatment" plot is very misleading because it fails to account for the significant circadian oscillation in this in vivo system.

Two previously synthesized and two structurally novel thiazoline iron chelators are described. N4-Benzyl-N1,N8-bis[[2-(2-hydroxyphenyl)thiazolin-4-yl]carbonyl] homospermidine (5) proved to be the most potent antiproliferative and cytocidal compound in the series with in vitro IC50 values of 3 and 1 microM on L1210 and P388 murine cell lines. The N4-acetyl analogue 7 was considerably less active than 5 with IC50 and cell viability values that were similar to those of the structurally simple thiazolines 2 and 3. The antiproliferative activity of 3 and 7 could be substantially reduced or ablated by delivery to cell suspensions as a 1:1 molar mixture with FeCl3, while the activity of 5 was unaffected by Fe(III) chelation. As expected, 3 induced a G1/S cell cycle block at the 100 microM block consistent with interference with DNA synthesis while 10 microM 5 did not affect L1210 cell cycle distribution. Tritiated thymidine incorporation studies confirmed that 5 was incapable of interfering with DNA synthesis at concentrations below 40 microM. Alkaline elution studies indicate that 5 does not cause DNA strand breaks in vitro at concentrations of 10 microM. The N4-benzyl group of 5 appears to impart in vitro potency as the N4-acetyl analogue 7 lacks comparable in vitro antiproliferative and cytocidal activity.

Adriamycin (ADR; 10 mg/kg) was given to mice bearing a 5-day-old Ehrlich ascites carcinoma (EAC) at two different circadian times: 05.00 and 17.00 h. The incorporation of tritiated thymidine into DNA (DNA synthetic activity; DNA-SA) was studied in the epithelium of the tongue, ileum, bone marrow and the EAC over a 120-hour period after treatment. ADR at 05.00 h was more perturbing of DNA-SA in the normal organs than was ADR at 17.00 h. ADR at 05.00 h caused greater inhibition of DNA-SA for longer periods of time than did ADR at 17.00 h. Thus, the point in the circadian system of the host when ADR was given significantly affected the result obtained in the normal organs. This was not true for the EAC. DNA-SA in the EAC responded in an almost identical manner regardless of whether the ADR was given at 05.00 or at 17.00 h.