D Schadendorf — Page 8

PubMedDate not supplied

Human melanoma cell lines selected in vitro displaying various levels of drug resistance against cisplatin, fotemustine, vindesine or etoposide: modulation of proto-oncogene expression.

Melanoma cells often display a multidrug-resistant phenotype, but the mechanisms involved are largely unknown. In order to establish a reproducable model system for studying the exact mechanisms conferring chemoresistance, we selected drug-resistant sublines in vitro derived from one parental human melanoma (MeWo) cell line. Four commonly used chemotherapeutic drugs (vindesine, etoposide, fotemustine, cisplatin) with different modes of action were choosen and stable sublines exhibiting four different levels of resistance against each drug were selected by continuous exposure over two years. Analysis of the drug-resistant sublines regarding their pharmacological characteristics and cross-resistance pattern revealed an up to 26-fold increased relative resistance against the alkylating agent fotemustine (MeWoFOTE) and an up to 35.7-fold increased relative resistance against topoisomerase-II-inhibiting etoposide (MeWoETO). Cisplatin selection (MeWoCIS) resulted in a 6-fold higher resistance compared to parental MeWo cells, whereas vindesine exposure (MeWoVIND) increased relative resistance up to 10.2-fold. Sublines selected separately for resistance to the DNA-damaging agents fotemustine, cisplatin and etoposide demonstrated strong cross-resistance. In comparison to the parental cell line drug-resistant sublines showed altered expression patterns of proto-oncogenes. Levels of p53 mRNA decreased with increasing resistance to vindesine, etoposide and fotemustine. Expression of bcl-2 family members (bax, bcl-x) was modulated by fotemustine, etoposide and cisplatin. In addition the expression of members of the fos (c-fos) and jun (c-jun, jun-D) gene family encoding transcription factors of the AP-1 complex was altered in all drug-resistant sublines. The pattern of expression varied with the inducing stimulus and this was paralleled by changes in the transactivation potential of AP-1. Our results reinforce the central role of AP-l in drug resistance probably through its participation in a programmed cellular stress response.

Antineoplastic Agents↗

PubMedDate not supplied

Intratumoral adoptive immunotherapy with tumor infiltrating lymphocytes (TIL) in a melanoma patient leading to regression of local tumor mass. A case report.

We describe a 52-year old man with a confined massive subcutaneous and intramuscular tumor metastasis on his back. He was treated with tumor-infiltrating lymphocytes (TIL) which were gained from the tumor of his back 3 months previously. Between 2.5 x 10(7) and 2 x 10(8) TIL were administered, five times at 2-week-intervals on day 2 in combination with a continuous subcutaneous infusion of interleukin(IL)-2 (1.8 x 10(6) IE/24 hours) over 3 days and a single intratumoral injection of a low dose of interferon(IFN)-alpha (1 x 10(6) IE) on day 1. There were no severe side effects. Immunotherapy led to a consistent regression of the tumor mass. After 3 months, treatment was discontinued due to the development of intracranial metastases. In parallel, due to an erythematous induration at the infusion site, it became increasingly difficult to infuse IL-2 subcutaneously. Additionally, high titers of anti-IL-2-antibodies were detected in serum. Following cessation of the immunotherapy and brain irradiation, the patient's clinical course has remained stable over the past 5 months, suggesting that small amounts of TIL with a low-dosed IL-2 may be helpful in the treatment of local tumor masses.

Drug Administration Schedule↗