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

2.50
Hdl Handle:
http://hdl.handle.net/10541/99942
Title:
Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma.
Authors:
Lee, Siow Ming; Margison, Geoffrey P; Woodcock, A A; Thatcher, Nick
Abstract:
There is increasing experimental evidence to suggest that expression of O6-alkylguanine-DNA-alkyltransferase (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 O6-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-1) 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 800 mg m-2 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 > or = 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.
Affiliation:
CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, U.K.
Citation:
Sequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma. 1993, 67 (6):1356-60 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
Jun-1993
URI:
http://hdl.handle.net/10541/99942
PubMed ID:
8512821
Type:
Article
Language:
en
ISSN:
0007-0920
Appears in Collections:
All Christie Publications ; All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorLee, Siow Mingen
dc.contributor.authorMargison, Geoffrey Pen
dc.contributor.authorWoodcock, A Aen
dc.contributor.authorThatcher, Nicken
dc.date.accessioned2010-05-27T15:00:17Z-
dc.date.available2010-05-27T15:00:17Z-
dc.date.issued1993-06-
dc.identifier.citationSequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma. 1993, 67 (6):1356-60 Br. J. Canceren
dc.identifier.issn0007-0920-
dc.identifier.pmid8512821-
dc.identifier.urihttp://hdl.handle.net/10541/99942-
dc.description.abstractThere is increasing experimental evidence to suggest that expression of O6-alkylguanine-DNA-alkyltransferase (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 O6-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-1) 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 800 mg m-2 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 > or = 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.en
dc.language.isoenen
dc.subject.meshAdolescent-
dc.subject.meshAdult-
dc.subject.meshAged-
dc.subject.meshAntineoplastic Agents-
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols-
dc.subject.meshDacarbazine-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshDrug Administration Schedule-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshMale-
dc.subject.meshMelanoma-
dc.subject.meshMiddle Aged-
dc.subject.meshNeutropenia-
dc.subject.meshNitrosourea Compounds-
dc.subject.meshOrganophosphorus Compounds-
dc.subject.meshRespiratory Distress Syndrome, Adult-
dc.subject.meshThrombocytopenia-
dc.titleSequential administration of varying doses of dacarbazine and fotemustine in advanced malignant melanoma.en
dc.typeArticleen
dc.contributor.departmentCRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, U.K.en
dc.identifier.journalBritish Journal of Canceren

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