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In Vitro and in Vivo Methazolastone-induced DNA Damage and Repair in L-1210 Leukemia Sensitive and Resistant to Chloroethylnitrosoureas¹

Istituto di Ricerche Farmacologiche "Mario Negri," via Eritrea 62, Milan [C. V. C., M. B., E. E., M. P., M. D.] and Istituto di Mutagenesi e Differenziamento- CNR, via Svezia 10, Pisa [L. M, L. C.], Italy

DNA damage caused by methazolastone [an analogue of 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide which does not require metabolic activation] was investigated in L-1210 leukemia which is sensitive to this drug and in a L-1210 subline [L-1210/N,N-bis(2-chloroethyl)-N-nitrosourea (BCNU)] which is resistant to both chloroethylnitrosoureas and methyltriazenes. Both in vitro and in vivo methazolastone caused formation of DNA alkali-labile sites (assessed by alkaline elution techniques) which were present in similar amounts and repaired at a similar rate in L-1210 and L-1210/BCNU. This suggests that these lesions are not crucial to methyltriazenes activity. DNA alkali-labile sites may be due to the removal of 7-methylguanine by 7-methylguanine-DNA glycosylase which showed the same activity in L-1210 and L-1210/BCNU.

Flow cytometry studies revealed that in L-1210 but not in L-1210/BCNU methazolastone induced an arrest of cells in SL-G₂-M phases. This blockade was delayed, occurring after at least two cell divisions after drug treatment and therefore appeared temporally unrelated to the presence of DNA alkali-labile sites.

There was three times more O⁶-methylguanine-DNA methyltransferase in L-1210/BCNU than in L-1210 suggesting that methylation of O⁶-guanine is an important lesion for methyltriazenes activity and resistance to this drug may be linked to its repair.

¹ This work was supported by the CNR (Italian National Research Council, Rome, Italy) "Progetto Oncologia", contract N.86.00653.44.

² To whom requests for reprints should be addressed.

Received 11/11/86. Revised 4/23/87. Accepted 6/19/87.

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