Susceptibility of human and murine drug-resistant tumor cells to the lytic activity of rIL2 - activated lymphocytes (LAK)

Gambacorti‐Passerini, Carlo; Rivoltini, Licia; Radrizzani, Marina; Supino, Rosanna; Mariani, Mariangela; Parmiani, Giorgio

doi:10.1007/bf00051374

Cited by 11 publications

(6 citation statements)

References 24 publications

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“…1). This is in agreement with the results of Gambacorti-Passerini et al [9] who showed that doxorubicin-resistant LoVo cells (LoVo/Dx) are more sensitive to lysis by rabbit complement than doxorubicinsensitive LoVo cells. Both KB-V1 and LoVo/Dx cells express numerous copies of P-gp on their surface, perhaps contributing to this increased susceptibility to complement-mediated lysis.…”

Section: Discussionsupporting

confidence: 93%

“…The interaction of MDR cells with complement is less well examined. A Dx-resistant LoVo subline was affected by antibody-and complementmediated lysis more than the Dx-sensitive subline [9].…”

Section: Introductionmentioning

confidence: 99%

“…MDR K562 human erythroleukemia cells were found to be more resistant to natural killer lymphocytes than drug-sensitive K562 cells [8]. In contrast, doxorubicin (Dx)-resistant LoVo human carcinoma, B16 mouse melanoma and 9229 human melanoma cells were significantly more affected by IL-Zactivated lymphocytes than their Dx-sensitive counterparts [9]. To date there is no consensus regarding the relative level of sensitivity of MDR cells to lymphocytoxicity, as some reports demonstrated enhanced or unaltered susceptibility whereas others showed enhanced resistance.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced sensitivity of P‐glycoprotein‐positive multidrug resistant tumor cells to complement‐mediated lysis

Bomstein¹,

Fishelson²

1997

Eur J Immunol

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The interaction of KB-V1, a multidrug resistant (MDR) variant of the KB-3-1 human oral carcinoma, with human complement was investigated. KB-V1 cells were found to be more sensitive than KB-3-1 cells to complement-mediated lysis. Detailed analysis of the capacity of KB cells to activate human complement demonstrated that both C3b deposition and formation of the membrane attack complex (MAC) are higher on KB-V1 than on KB-3-1 cells. Furthermore, the MAC formed on KB-V1 cells, but not on KB-3-1 cells, was found to be resistant to trypsin treatment, i.e. more stably inserted into the plasma membrane. Immunofluorescence analysis by flow cytometry showed that KB-V1 cells express less decay-accelerating factor (DAF, CD55) than KB-3-1 cells. Two other complement regulatory proteins, membrane cofactor protein (MCP, CD46) and CD59 are expressed to a similar extent on both KB-V1 and KB-3-1 cells. Treatment of KB-V1 cells with neutralizing anti-P-glycoprotein (P-gp) monoclonal antibodies reduced their sensitivity to complement. In addition, KB-V1 revertants which cease to express P-gp become more resistant to complement. These results indicate that multiple factors, such as reduced expression of DAF, enhanced deposition of C3b and increased binding and stability of the MAC may contribute to the increased complement sensitivity of KB-V1 cells. It is suggested that P-gp is responsible for the complement-sensitive phenotype of KB-V1 cells.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Enhanced sensitivity of P‐glycoprotein‐positive multidrug resistant tumor cells to complement‐mediated lysis

Bomstein¹,

Fishelson²

1997

Eur J Immunol

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“…LAK cells are fully effective in reducing colony formation of a P-glycoprotein-positive (human myelomonocytic) K562 subline (Ohtsu et al, 1990). Taken together with the data from recent LAK cell studies with colo-intestinal tumor cell couples, and an independently derived MCF7 MDR subline (Allavena et al, 1989;Gambacorti-Passerini et al, 1988), evidence is compelling that in human clinical multi-drug-resistance there is no reduced susceptibility for NK-or LAK-cell function. This conclusion is even more justified, as in the present study we included multi-drug-resistant sublines not over-expressing Pglycoprotein.…”

Section: Discussionmentioning

confidence: 96%

“…An increased density of P-170 molecules could interfere with the expression of cellular adhesion molecules or with subsequent steps required for cell death. Without providing data on the expression of P-glycoprotein or relevant cell-adhesion molecules, other studies either supported (Yanovich et al, 1986), or refuted (Allavena et al, 1989;Gambacorti-Passerini et al, 1988) MDR-related tumor-cell resistance to LAK cells.…”

mentioning

confidence: 99%

Altered expression of P‐glycoprotein and cellular adhesion molecules on human multi‐drug‐resistant tumor cells does not affect their susceptibility to NK‐ and LAK‐mediated cytotoxicity

Scheper

Dalton

Grogan

et al. 1991

Intl Journal of Cancer

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Drug resistance has been associated with resistance to NK- and LAK-cell-mediated cytotoxicity. We evaluated this issue in human cell lines, using multiple myeloma cells (8226) and 2 multi-drug-resistant (MDR) sublines selected using doxorubicin (8226/Dox40) and mitoxantrone (8226/MR40). In parallel, we studied the human breast carcinoma cell line series MCF7, MCF7/D40 and MCF7/Mitox. Unlike the sensitive parental cell lines, all 4 sublines display MDR-patterns of resistance, with the P-glycoprotein pump (P-170) detected only in the doxorubicin-selected sublines. Flow cytometric and immunocytochemical analyses showed expression of cellular adhesion molecules ICAM-I and LFA-3, and MHC-Class-I (MCF7/D40 only), to be decreased in the doxorubicin-selected MDR-sublines, whereas expression of CD56 (Leu 19) was strongly up-regulated in 8226/Dox40. Lysis of P-170-positive MDR tumor cells by NK or LAK cells was, however, unaffected by these alterations, suggesting redundancy in effector:target-cell adhesion pathways. Mitoxantrone-selected tumor cells did not display P-170, nor did they show altered expression of cellular adhesion molecules. Their susceptibility to NK or LAK cytolysis was also unimpaired as compared to the parental cell lines. Clinically, these results imply that immunotherapeutic modalities aiming at increased natural killer functions deserve full consideration even in patients who have become refractory to further cytostatic drug treatment.

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Generation and partial characterization of melanoma sublines resistant to lymphokine activated killer (LAK) cells. Relevance to doxorubicin resistance

Rivoltini

Gambacorti‐Passerini²,

Supino

et al. 1989

Intl Journal of Cancer

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To see whether a tumor cell population may contain cells resistant to lymphokine-activated killer (LAK) lymphocytes, cells from a LAK-sensitive melanoma line (Me 665/2) were co-cultured with LAKs. Three sublines were obtained after 1, 2 or 3 immunoselection cycles. Immunoselected (IS) sublines show reduced proliferation, decreased reactivity to the monoclonal antibody (MAb) R24 and appeared morphologically more differentiated in comparison with the parental Me 665/2 line. A progressively reduced sensitivity to LAKs was observed in IS sublines with a more than 8-fold reduction in LAK susceptibility. A reduced complement (C)-mediated lysis was also observed in IS sublines. Since we have previously shown that LAK sensitivity of melanoma cells may be associated with Doxorubicin (Dx) resistance, the sensitivity to Dx was tested in these lines. An augmented sensitivity to Dx was noted in IS sublines as compared with Me 665/2. The differences in LAK susceptibility between the IS sublines and the parental Me 665/2 line remained stable for 2 weeks but declined and disappeared thereafter. These results indicate that (1) a LAK-sensitive tumor line may contain a subpopulation of cells which are significantly less lysed by LAKs; (2) a correlation between LAK sensitivity and susceptibility to C-mediated lysis is also present; and (3) increased sensitivity to Dx is evident in the IS sublines.

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Susceptibility of human and murine drug-resistant tumor cells to the lytic activity of rIL2 - activated lymphocytes (LAK)

Cited by 11 publications

References 24 publications

Enhanced sensitivity of P‐glycoprotein‐positive multidrug resistant tumor cells to complement‐mediated lysis

Enhanced sensitivity of P‐glycoprotein‐positive multidrug resistant tumor cells to complement‐mediated lysis

Altered expression of P‐glycoprotein and cellular adhesion molecules on human multi‐drug‐resistant tumor cells does not affect their susceptibility to NK‐ and LAK‐mediated cytotoxicity

Generation and partial characterization of melanoma sublines resistant to lymphokine activated killer (LAK) cells. Relevance to doxorubicin resistance

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