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Penetration of dacarbazine and its active metabolite 5‐aminoimidazole‐4‐carboxamide into cutaneous metastases of human malignant melanoma
Author(s) -
Joukhadar Christian,
Klein Nikolas,
Mader Robert M.,
Schrolnberger Claudia,
Rizovski Blanka,
HeereRess Elisabeth,
Pehamberger Hubert,
Strauchmann Nadja,
Jansen Burkhard,
Müller Markus
Publication year - 2001
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20011015)92:8<2190::aid-cncr1562>3.0.co;2-2
Subject(s) - dacarbazine , melanoma , medicine , metabolite , area under the curve , pharmacokinetics , pharmacology , microdialysis , oncology , cancer research , central nervous system
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. Cancer 2001;92:2190–6. © 2001 American Cancer Society.