Mechanism of the anti-tumour effect of biochemotherapy in melanoma: preliminary results

Melanoma Res. 1994 Oct;4(5):327-30. doi: 10.1097/00008390-199410000-00010.

Abstract

During the conduct of a biochemotherapy trial in which cisplatin, vinblastine and dacarbazine (CVD) were administered concurrently with interleukin-2 (IL-2) plus interferon-alpha 2a (IFN-alpha 2a) (biochemotherapy) in advanced melanoma, we performed a series of laboratory studies in an attempt to understand better the mechanism of anti-tumour effect of the regimen. We initially hypothesized that CVD enhanced the anti-tumour effect of the biotherapy. However, in the first 10 patients studied, of whom eight were responders, we observed no lymphokine-associated killer cell (LAK) and minimal natural killer (NK) cell activities. This prompted us to change our initial hypothesis. Based on the work of others which showed a marked synergism between IL-1 alpha and cisplatin, apparently mediated by H2O2 derived from tumour-infiltrating macrophages, we reasoned that the biotherapy could enhance the cytotoxicity of the CVD regimen. To evaluate macrophage function, we measured serum neopterin levels in eight responders and seven non-responders. An increase of six or more times above baseline levels was observed in seven out of eight responders but in only two of seven non-responders (P = 0.041). We also examined the level of DNA inter-strand cross-link in peripheral blood mononuclear cells in four responders and four responders, as a means to evaluate the DNA repair process. A DNA cross-link index > or = 0.75 was observed in all four responders but only in one non-responder (P = 0.14). Our preliminary results suggest that concurrent biochemotherapy may exert its predominant anti-tumour effect by direct cytotoxicity and that macrophages may be involved in this process.

Publication types

  • Clinical Trial

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Cisplatin / administration & dosage
  • Cisplatin / pharmacology
  • Cross-Linking Reagents / pharmacology
  • DNA Damage
  • DNA, Neoplasm / drug effects
  • Dacarbazine / administration & dosage
  • Dacarbazine / pharmacology
  • Drug Synergism
  • Humans
  • Immunologic Factors / pharmacology
  • Immunologic Factors / therapeutic use*
  • Interferon alpha-2
  • Interferon-alpha / pharmacology
  • Interferon-alpha / therapeutic use*
  • Interleukin-2 / pharmacology
  • Interleukin-2 / therapeutic use*
  • Killer Cells, Lymphokine-Activated / drug effects
  • Killer Cells, Natural / immunology
  • Macrophage Activation / drug effects
  • Melanoma / drug therapy
  • Melanoma / immunology
  • Melanoma / secondary
  • Melanoma / therapy*
  • Models, Biological
  • Recombinant Proteins
  • Vinblastine / administration & dosage
  • Vinblastine / pharmacology

Substances

  • Cross-Linking Reagents
  • DNA, Neoplasm
  • Immunologic Factors
  • Interferon alpha-2
  • Interferon-alpha
  • Interleukin-2
  • Recombinant Proteins
  • Vinblastine
  • Dacarbazine
  • Cisplatin