Cells L1210 mutants

In assays against cultured L1210/R81 cells [43], a resistant mutant with a severe defect in MTX active transport combined with a 35-fold increase in DHFR with normal MTX affinity [49], (III. 147) was found to have an IC50 value of 46 /rM as compared with 205 /iM for MTX. Similar incomplete cross resistance was observed between MTX and the 5-substituted quinazolines (III.148) and (III.149). From these results it would seem that the 5,8-dideaza compounds may be taken up better than MTX by the MTX-resistant cells. 

Interestingly, substitution of the L-Arg residue in nodularin with L-Val (trivially named mutoporin) leads to biological properties which are somewhat different from those of other nodularins. This variant exerts cytotoxicity against tumour cell lines (49), a property not shown by nodularin. Derivatization of the Arg residue in nodularin with acetylacetone to produce the dimethylpyrimidyl-analog led to similar results as the new compound was found to be cytotoxic to L1210 cells (53). Probably this cytotoxicity is also exerted by the microcystin mutants with both the X and Y position occupied by hydrophobic residues. 

Fig. 3. DNA ligase I and II activity in wild-type L1210 cells (upper panel) and in variant (mutant) 3 Qower panel) cells. The ligases were separated on an hydroxylapatite column as described in [12]. Upper panel wild-type CQ h lo erpanel variant (mutant) 3 cells. DNA ligase activity, Oprotein concentration...

Isolation of a DNA Ligase Mutant from L1210 Cells... 

In conclusion, we have isolated a variant (mutant) from wild-t e L1210 cells which is insensitive to SAB potentiation of DMS cytotoxicity. This variant is independent confirmatory evidence of ADPRT involvement in DNA repair and indicates that 3-aminobenzamide sensitivity is related to DNA Ugase activity. 

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