Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma

Abstract

Summary There is increasing experimental evidence to suggest that expression of 06-alkylguanine-DNAalkyltransferase (ATase) is a major factor in resistance to dacarbazine (DTIC). We recently demonstrated a progressive ATase depletion in human peripheral lymphocytes with nadir levels occurring at 4-6 h after DTIC administration (Lee et al., 1991). Therefore in an attempt to improve the clinical response rate of DTIC, fotemustine was administered 4 h after DTIC administration; since in the case of fotemustine, ATase removes the chloroethyl lesions from the 06-position of guanine, thereby preventing the formation of the cytotoxic cross-links. Sixty patients with widely metastatic melanoma received DTIC at 400, 500 or 800 mg m-2 followed by fotemustine (100 mg m') at 4 h after DTIC administration. Treatment was repeated every 28 days with a total of 169 cycles of chemotherapy administered; 75, 57 and 37 treatment cycles with 400, 500 and 800mg m2 DTIC groups respectively. Eighteen of the 60 patients responded (with three complete response); response rates were linearly related to dose, being 24%, 30% and 40% in patients receiving 400, 500 and 800 mg m-2 of DTIC respectively and the overall response rate was 30%. Median survival was 3.6 months (range, 1-15 months) with no statistically significant difference between the different DTIC treatment groups (P = 0.67). Nine patients are alive at 5 to 26 months (median 10 months); three patients with no tumour and five patients with stable disease. A statistically significant relationship was seen between the development of severe haematological toxicity (WHO > 3) with increasing dosage of DTIC and significant subclinical pulmonary damage was seen in 11 patients where the lung function was monitored during the course of treatment. In conclusion, it appears that with this small group of patients, escalation of DTIC dosage might not significantly affect response rates but does increase haematological toxicity. The present study provides a framework for other studies in an attempt to modulate ATase-mediated drug resistance in tumour tissues but the associated toxicity will need careful monitoring.

Inactivation of O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells by temozolomide

“…Indeed, in the treatment of melanoma with DTIC/fotemustine combinations, the schedule of fotemustine 4 h after DTIC was designed to exploit the anticipated nadir of ATase activity produced by DTIC (Lee et al, 1991) and produces better response rates than the individual agents given alone (Lee et al, 1993b). The possibility therefore of giving a chloroethylating agent 2-6 h after the last of five doses of temozolomide given every 2-6 h also seems worthy of consideration.…”

O6-methylguanine-DNA methyltransferase depletion and DNA damage in patients with melanoma treated with temozolomide alone or with lomeguatrib

“…The methylating agent generates O 6 -meG in DNA and this consumes MGMT in being repaired, rendering the cell susceptible to the nitrosourea (Lee et al, 1993;Smith et al, 1996;Schold et al, 2000). Such combinations proved to be unacceptably toxic in clinical trials (Gerard et al, 1993;Clemons et al, 2003).…”

Repair of O6-alkylguanines in the nuclear DNA of human lymphocytes and leukaemic cells: analysis at the single-cell level

“…no major variations were observed regarding the persistence of o6-EtGua in cells isolated from the same donor at different times over a period of 1 week, although the distributions of t1 values became somewhat broader (± 25% of the mean) during long-term observations for up to several months. In contrast, the persistence of 06-EtGua in nuclear DNA of lymphocytes and leukaemic blasts exhibited wide inter- Leung, 1986;Sagher et al, 1988;Strauss, 1990;Lee et al, 1991;Souliotis et al, 1991) After blocking cellular AT activity by preincubating cells with 06-BeGua, elimination of 06-EtGua from DNA of normal and leukaemic lymphocytes was decelerated considerably, but not entirely abolished. Thus, after reducing the level of active AT by 06-BeGua to 1% of untreated controls (Table I), 06-EtGua was still repaired with t, = 4 h in a sample of normal lymphocytes (Figure 7).…”

“…Moreover, considerable inter-individual variability has been observed for a given type of cells (Kyrtopoulos et al, 1990; Strauss, 1990;Citron et al, 1991;Redmond et al, 1991). Thus, in peripheral human lymphocytes inter-patient variations in AT levels up to a factor of 9 have been reported (Sagher et al, 1988;Gerson, 1989;Lee et al, 1991;Panella et al, 1992). Plausible relationships have been proposed between cell type and individual sensitivity to the cytotoxic effects of alkylating or chloroalkylating agents on the one hand and the levels of cellular AT activity on the other (Brent et al, 1985;Dolan et al, 1989;Pieper et al, 1991;Panella et al, 1992).…”