Cellular resistance to the antimelanoma immunotoxin ZME-gelonin and strategies to target resistant cells |
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Authors: | M G Rosenblum Lawrence Cheung S K Kim Kalpana Mujoo Nicholas J Donato James L Murray |
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Institution: | (1) Department of Clinical Immunology and Biological Therapy, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 041, Houston, TX 77030, USA Fax: (713)794 4261, US |
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Abstract: | The development of cellular resistance to immunotoxins has been demonstrated in a variety of models and can involve a number
of mechanisms. For the present study, an immunotoxin was utilized composed of an antimelanoma antibody ZME-018 recognizing
a 240-kDa surface glycoprotein (gp 240) and the plant toxin gelonin. Human melanoma cells (A375-M) were grown in the presence
of increasing amounts of ZME-gelonin and a clonal variant (A-375-ZR) was developed that was 100-fold resistant to ZME-gelonin
compared to parental cells. Scatchard analysis showed that the A375-M parental cells had 260×103 ZME-gelonin-binding sites/cell with relatively low affinity (5 nM). In contrast, resistant A375-ZR cells demonstrated a reduced
number of low-affinity sites (160×103/cell), but showed a small number (47×103) of higher-affinity sites (0.8 nM). Internalization rates and degradation rates of 125I-labeled ZME-gelonin were identical in both the parental and resistant cells. A375-ZR cells were found to be more resistant
to vincristine and doxorubicin than were parental cells. Both cell lines were almost equally sensitive to native gelonin,
5-fluorouracil (5-FU), cisplatin, melphalan, carmustine, interferon γ (IFNγ) and IFNα. In addition, both cell lines were equally
sensitive to another gelonin-antibody conjugate that binds to cell-surface, GD2 (antibody 14G2A). However, resistant cells were twice as sensitive to the cytotoxic effects of etoposide than were parental cells. Finally,
a variety of agents were tested in combination with ZME-gelonin against A375-ZR cells in an attempt to identify agents to
augment immunotoxin cytotoxic effects against resistant cells. The agents 5-FU, cisplatin, IFNγ, IFNα, and etoposide were
the most effective in augmenting the cytotoxicity of ZME-gelonin against resistant cells. These studies suggest that development
of resistance to one immunotoxin does not cause development of cross-resistance to other gelonin immunotoxins. Further, specific
biological response modifiers and chemotherapeutic agents may be effective in augmenting the effectiveness of immunotoxins
and specifically targeting or reducing the emergence of immunotoxin-resistant cells.
Received: 15 March 1995 / Accepted: 28 November 1995 |
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Keywords: | Gelonin Immunotoxins Chemotherapeutic agents Drug resistance Melanoma |
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