Abstract
Resistance to alkylating agents is partly due to the presence of the DNA repair enzyme, termed O6 alkyltransferase (O6AT). Preclinical evidence of the transient restoration of sensitivity of cells resistant to nitrosoureas by pretreatment with a methylating agent, whose role is to deplete cells of O6AT activity and clinical evidence of such a depletion in patients lymphocytes, led us to test the sequential administration of dacarbazine 3 h prior to fotemustine, a chloroethylnitrosourea derivative. 24 patients with measurable advanced melanoma entered the trial and are evaluable. Toxicity was mainly haematological with early neutropenia and/or thrombocytopenia. Clinical activity (33%) was impressive especially on lung metastases with high complete response rate for that site (7/14). Unfortunately, the occurrence of a rapidly fatal pulmonary toxicity precludes further use of the regimen before a plausible explanation for this unexpected toxicity is obtained. Indeed, similar cases have been reported in other trials using the sequential schedule while no lung toxicity was reported in single agent or alternated administrations. Preclinical studies are ongoing to test the hypothesis of a glutathione depletion and the possibility of a rescue treatment.
| Original language | English |
|---|---|
| Pages (from-to) | 447-450 |
| Number of pages | 4 |
| Journal | European Journal of Cancer |
| Volume | 28 |
| Issue number | 2-3 |
| DOIs | |
| Publication status | Published - 1992 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
Cite this
Sequential administration of dacarbazine and fotemustine in patients with disseminated malignant melanoma-an effective combination with unexpected toxicity. / Aamdal, S.; Bohman, T.; Gerard, B.; D'Incalci, M.
In: European Journal of Cancer, Vol. 28, No. 2-3, 1992, p. 447-450.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Sequential administration of dacarbazine and fotemustine in patients with disseminated malignant melanoma-an effective combination with unexpected toxicity
AU - Aamdal, S.
AU - Bohman, T.
AU - Gerard, B.
AU - D'Incalci, M.
PY - 1992
Y1 - 1992
N2 - Resistance to alkylating agents is partly due to the presence of the DNA repair enzyme, termed O6 alkyltransferase (O6AT). Preclinical evidence of the transient restoration of sensitivity of cells resistant to nitrosoureas by pretreatment with a methylating agent, whose role is to deplete cells of O6AT activity and clinical evidence of such a depletion in patients lymphocytes, led us to test the sequential administration of dacarbazine 3 h prior to fotemustine, a chloroethylnitrosourea derivative. 24 patients with measurable advanced melanoma entered the trial and are evaluable. Toxicity was mainly haematological with early neutropenia and/or thrombocytopenia. Clinical activity (33%) was impressive especially on lung metastases with high complete response rate for that site (7/14). Unfortunately, the occurrence of a rapidly fatal pulmonary toxicity precludes further use of the regimen before a plausible explanation for this unexpected toxicity is obtained. Indeed, similar cases have been reported in other trials using the sequential schedule while no lung toxicity was reported in single agent or alternated administrations. Preclinical studies are ongoing to test the hypothesis of a glutathione depletion and the possibility of a rescue treatment.
AB - Resistance to alkylating agents is partly due to the presence of the DNA repair enzyme, termed O6 alkyltransferase (O6AT). Preclinical evidence of the transient restoration of sensitivity of cells resistant to nitrosoureas by pretreatment with a methylating agent, whose role is to deplete cells of O6AT activity and clinical evidence of such a depletion in patients lymphocytes, led us to test the sequential administration of dacarbazine 3 h prior to fotemustine, a chloroethylnitrosourea derivative. 24 patients with measurable advanced melanoma entered the trial and are evaluable. Toxicity was mainly haematological with early neutropenia and/or thrombocytopenia. Clinical activity (33%) was impressive especially on lung metastases with high complete response rate for that site (7/14). Unfortunately, the occurrence of a rapidly fatal pulmonary toxicity precludes further use of the regimen before a plausible explanation for this unexpected toxicity is obtained. Indeed, similar cases have been reported in other trials using the sequential schedule while no lung toxicity was reported in single agent or alternated administrations. Preclinical studies are ongoing to test the hypothesis of a glutathione depletion and the possibility of a rescue treatment.
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U2 - 10.1016/S0959-8049(05)80074-7
DO - 10.1016/S0959-8049(05)80074-7
M3 - Article
C2 - 1591062
AN - SCOPUS:0026586976
VL - 28
SP - 447
EP - 450
JO - European Journal of Cancer
JF - European Journal of Cancer
SN - 0959-8049
IS - 2-3
ER -