Mechanism of the anti-tumour effect of biochemotherapy in melanoma: preliminary results.
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.
Buzaid
A C
AC
Department of Melanoma/Sarcoma, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Grimm
E A
EA
Ali-Osman
F
F
Ring
S
S
Eton
O
O
Papadopoulos
N E
NE
Bedikian
A
A
Plager
C
C
Legha
S S
SS
Benjamin
R
R
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D003606:Dacarbazine / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000494:pharmacology / Q000627:therapeutic use*; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects; D007694:Killer Cells, Natural / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008954:Models, Biological; D011994:Recombinant Proteins; D014747:Vinblastine / Q000008:administration & dosage / Q000494:pharmacology
D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D007155:Immunologic Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D014747:Vinblastine; D003606:Dacarbazine; D002945:Cisplatin