Tumour eradication with high-dose idarubicin-anti-Ly-2.1 with murine tumour necrosis factor-alpha in mice.
The antitumour efficacy of Ida-anti-Ly-2.1 immunoconjugate in combination with murine TNF-alpha (mTNF-alpha) has been evaluated in a disseminated murine thymic lymphoma model E3. This tumour model shows characteristics similar to lymphoma in humans with widely disseminated tumour in major organs. In vitro both idarubicin (Ida) and Ida-anti-Ly-2.1 showed additive and synergistic cytotoxic effects, respectively, with mTNF-alpha when tested using the isobolagram method. Similar synergistic effects were also seen in vivo. Tumour-bearing mice were treated with various doses of mTNF-alpha and Ida alone, however, neither showed a therapeutic response in mice. When mice were treated with Ida-anti-Ly-2.1 'early' the median survival time (MST) was increased by 8 days, however, 'late' treatment was ineffective. Combination therapy of mTNF-alpha and Ida-anti-Ly-2.1 conjugate (42 micrograms) given 'early' was capable of curing 50% of mice. However, when tumour-bearing mice were given a high dose (234 micrograms) of Ida-anti-Ly-2.1 together with mTNF-alpha 100% of mice survived disease free. Such an effect was not observed when free mTNF-alpha, Ida-anti-Ly-2.1, anti-Ly-2.1 or a mixture of anti-Ly-2.1+mTNF-alpha was given at the same dose. These results show that a combination of very toxic drug immunoconjugates and TNF could lead to the eradication of disseminated tumour in mice and may be relevant for the treatment of minimal residual disease in cancer patients.
Pietersz
G A
GA
Austin Research Institute, Austin Hospital, Heidelberg, Victoria, Australia.
Bogdanovski
M
M
Li
W
W
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000950:Antigens, Ly; D004357:Drug Synergism; D006801:Humans; D015255:Idarubicin / Q000008:administration & dosage*; D018796:Immunoconjugates / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013945:Thymoma / Q000628:therapy*; D013953:Thymus Neoplasms / Q000628:therapy*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage*
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D018796:Immunoconjugates; D014409:Tumor Necrosis Factor-alpha; D015255:Idarubicin