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The multidrug resistance (MDR)-neutralizing and cytotoxic properties of 16 novel tetramethylpiperidine (TMP)-substituted phenazines were compared with those of clofazimine and B669 using a P-glycoprotein (P-gp)-expressing undifferentiated, human leukemia cell line (K562/MMB). Unchlorinated TMP-substituted phenazine molecules were more cytotoxic than their chlorinated counterparts, while the halogenated molecules, especially those with chlorine atoms at position 3 on the aniline and phenyl rings, were less cytotoxic but more effective as chemosensitizing, P-gp-neutralizing agents. One of the TMP-substituted phenazines, B4121, increased the sensitivity of K562/MMB cells to vinblastine by 100-fold. TMP-substituted phenazines are a novel class of pharmacologic anti-cancer agents with both direct cytotoxic, as well as MDR-neutralizing anti-tumor properties.

At concentrations of 0.5 μM and upward, cyclosporin A (CsA) caused dose-related inhibition of the growth of a hamster renal tubular cell line (HAK ATCC; CCL15) in vitro . Inhibition of cell growth was due to the cytotoxic properties of CsA which were associated with enhancement of activity of phospholipase A 2 (PLA 2 ) according to the increased generation of arachidonic acid and lysophosphatidylcholine (LPC). Arachidonate per se, at concentrations of up to 20 μM, did not affect the growth of HAK cells, while cyclooxygenase and 5-lipoxygenase inhibitors failed to protect the cells against the antiproliferative effects of CsA. However, LPC caused dose-related inhibition of the growth of HAK cells. Moreover, coincubation with lysophospholipase or α-tocopherol (AT, vitamin E), a PLA 2 inhibitory and lysophospholipid-complexing agent, protected the HAK cells against both CsA and LPC. The Na + , K + -ATPase activity of HAK cells was also inhibited by CsA, with the enzyme being protected by inclusion of AT or lysophospholipase. Increased activity of PLA 2 and inhibition of Na + , K + -ATPase preceded cytotoxicity and cytolysis. Excessive production of lysophospholipids and consequent inhibition of Na + , K + -ATPase in renal tubular cells is a possible mechanism of CsA-induced nephrotoxicity. The protective effects of AT suggest that this agent may be clinically useful in preventing the renal side effects of CsA.