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Cancer Chemotherapy and Pharmacology

, Volume 31, Issue 3, pp 240–246 | Cite as

In vivo depletion of O6-alkylguanine-DNA-alkyltransferase in lymphocytes and melanoma of patients treated with CB 10-277, a new DTIC analogue

  • Siow Ming Lee
  • Nick Thatcher
  • Derek Crowther
  • Geoffrey P Margison
Original Articles O6-Alkylguanine-DNA-Alkyltransferase, Lymphocytes, Melanoma, CB10-277, DTIC Analogue

Summary

there is increasing evidence to suggest that alkylation of guanine residues in DNA at the O6 position is the critical cytotoxic event following treatment with dacarbazine (DTIC) and related drugs and that endogenous O6-alkylguanine-DNA alkyltransferase (ATase) gene expression may be a major factor in resistance to such agents. 1-p-Carboxyl-3,3-dimethylphenyltriazene (CB 10-277) was recently selected for clinical evaluation as a DTIC analogue with improved solubility, stability and (possibly) metabolic activation. Serial ATase levels were measured in peripheral blood lymphocytes of nine patients and in biopsied melanoma samples of two patients undergoing treatment with 24-h continuous infusion of CB 10-277 (12 g/m2). Wide individual variations in pre-treatment levels as well as in the post-treatment depletion of lymphocyte ATase were seen. Progressive depletion of lymphocyte ATase was seen during continuous infusion of CB 10-277 in all patients. Complete suppression of lymphocyte ATase activity occurred in two patients whose pre-treatment ATase levels were low. Immediately following completion of the CB 10-277 infusion, the median ATase activity was 17% of pre-treatment levels (range, 0–67%). At 24 h after the end of the infusion, no recovery of lymphocyte ATase activity was observed in six patients, but significant recovery to 50%, 100% and 102% of pre-treatment activity occurred in the other three. In three patients who returned for subsequent cycles of chemotherapy at 4 weeks after the first dose, pre-treatment ATase levels showed a 3-to 4-fold increase relative to the original pre-treatment values. A significant correlation was found between the extent of ATase depletion and the initial lymphocyte ATase levels (r=0.725,P<0.05). Haematological toxicity developed in two patients and was associated with low pre-treatment ATase activity. Depletion of tumour ATase activity was noted in these patients, with residual activity amounting to 8% and 11% of pre-treatment levels, respectively, in the biopsied melanoma tissues. These results indicate extensive metabolism of CB 10-277 to a methylating agent capable of mediating alkylation of DNA and subsequent depletion of lymphocyte and tumor ATase levels and further indicate that the effects on lymphocytes may reflect effects on the target tumour.

Keywords

Melanoma Guanine Continuous Infusion Peripheral Blood Lymphocyte Dacarbazine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ATase

O6-alkylguanine-DNA alkyltransferase

CB 10-277

1-p-carboxyl-3,3-dimethylphenyltriazene

DTIC

dacarbazine, 5-(3,3-dimethyl-1-triazeno)imidazole-4-carboxamide

MTIC

5-(3-methyl-1-triazeno)imidazole-4-carboxamide

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Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Siow Ming Lee
    • 1
    • 2
  • Nick Thatcher
    • 1
  • Derek Crowther
    • 1
  • Geoffrey P Margison
    • 2
  1. 1.CRC Department of Medical OncologyChristie Hospital NHS TrustManchesterUK
  2. 2.CRC Department of CarcinogenesisPaterson Institute for Cancer ResearchManchesterUK

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