Penetration of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide into cutaneous metastases of human malignant melanoma.
BACKGROUND
Dacarbazine has been on the market for approximately 3 decades but remains the most effective single agent available for the therapy of metastatic malignant melanoma (MMM). Most MMMs, however, respond poorly to dacarbazine therapy. Apart from tumor resistance at a molecular level, several studies support the notion that therapeutic failure in tumor therapy also might be attributed to an impaired transcapillary drug transfer.


METHODS
On the basis of this hypothesis, the authors measured intratumor transcapillary transfer rates of dacarbazine and its active metabolite 5-aminoimidazole-4-carboxamide (AIC) by in vivo microdialysis after intravenous administration of dacarbazine at doses of 200 mg/m(2) to 1000 mg/m(2) (n = 7) in patients suffering from MMM.


RESULTS
For all doses, area under the concentration curve (AUC) values for dacarbazine and AIC were not significantly different between plasma and tumor interstitium with AUC(tumor)/AUC(plasma) ratios of 0.97 +/- 0.08 (mean +/- standard error of the mean) for dacarbazine and 0.76 +/- 0.22 for AIC. AUC(0-240) values for dacarbazine and AIC measured in plasma correlated closely with corresponding AUC(0-240)values measured in the interstitium of MMMs with values of r(s) = 0.82 (P = 0.042) and r(s) = 0.90 (P = 0.037), respectively.


CONCLUSIONS
The results of this study indicate favorable tumor penetration characteristics of dacarbazine and its active metabolite AIC. The relative lack of response to antineoplastic therapy with dacarbazine, thus might be explained by resistance of melanoma cells at a molecular level rather than by an inability of dacarbazine and AIC to penetrate into the interstitium of MMM.
Joukhadar
C
C
Department of Clinical Pharmacology, Division of Clinical Pharmacokinetics, University of Vienna Medical School, Vienna, Austria.
Klein
N
N
Mader
R M
RM
Schrolnberger
C
C
Rizovski
B
B
Heere-Ress
E
E
Pehamberger
H
H
Strauchmann
N
N
Jansen
B
B
Müller
M
M
D000368:Aged; D000620:Aminoimidazole Carboxamide / Q000378:metabolism; D018906:Antineoplastic Agents, Alkylating / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D003606:Dacarbazine / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000556:secondary; D017551:Microdialysis; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D018906:Antineoplastic Agents, Alkylating; D000620:Aminoimidazole Carboxamide; D003606:Dacarbazine