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Augmentation of Antitumor Efficacy by the Combination of Recombinant Tumor Necrosis Factor and Chemotherapeutic Agents in Vivo

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892

We evaluated the in vivo antitumor effects of the combination of recombinant human tumor necrosis factor (rhTNF) and three chemotherapeutic agents in an established murine tumor model. C57BL/6 mice bearing a subdermal weakly immunogenic 3-methylcholanthrene-induced sarcoma (MCA-106) received one i.v. dose of cyclophosphamide (Cy) (100 mg/kg), doxorubicin (5 mg/kg), or 5-fluorouracil (75 mg/kg) on either Day 8, 10, or 12. All animals received one i.v. dose of rhTNF (4 or 6 µg/mouse) on Day 10. The most effective time for administration of the chemotherapeutic agent was determined to be 48 h following rhTNF administration of all agents tested. The combined results of four separate experiments evaluating tumor size on Day 28 following tumor inoculation revealed that the groups treated with 4 or 6 µg of rhTNF and Cy (on Day 12) had tumor size reductions of 70 and 94%, respectively, compared to untreated controls (P² < 0.005). Mice treated with Cy alone, or with 4 or 6 µg of rhTNF alone had tumor size reductions of 30, 35, and 41%, respectively, compared to untreated controls (P² < 0.02). Analysis of cure rates demonstrates that the combination of Cy with 4 or 6 µg tumor necrosis factor cured 35 and 48% of the animals, respectively (P² < 0.01), compared to 10, 0, and 14% of mice treated with single agent Cy, 4 µg rhTNF, or 6 µg rhTNF, respectively. The timing of Cy and TNF administration was critical since administration of Cy prior to or concurrent with rhTNF was not effective in reducing tumor area or increasing cure rates over those achieved with either agent alone. Mice treated with doxorubicin alone had an increase in tumor size of 139 ± 29% over untreated controls (P² < 0.05) on Day 28 following tumor inoculation and none were cured. In contrast, mice treated with doxorubicin plus 4 or 6 µg rhTNF exhibited early reductions in tumor size such that on Day 28 the average tumor areas were decreased by 66 ± 34% (P² < 0.05) and 73 ± 1% (P² < 0.02) of untreated controls with cure rates of 29% and 43% (P² < 0.02), respectively. However, the combination of 6 µg rhTNF plus doxorubicin led to substantial lethal toxicity with only 29% of mice surviving treatment. 5-Fluorouracil alone resulted in an increase in tumor area of 164% (P² < 0.05) over that of untreated controls on Day 28 following tumor inoculation. Mice treated with the combination of 5-fluorouracil plus 4 or 6 µg rhTNF had only small reductions in tumor area by 38% (P² < 0.05) and 20% (P² < 0.05) of untreated controls, with cure rates of 17 and 0% (P² > 0.05). Finally, attempts to treat mice bearing a nonimmunogenic sarcoma (MCA-102) by combination therapy with rhTNF plus Cy failed. This study demonstrates that the administration of certain chemotherapeutic agents, particularly Cy, following rhTNF can result in a combined antitumor effect against a weakly immunogenic sarcoma and serves as a rationale for clinical trials employing the combination of rhTNF and chemotherapy in patients with cancer.

¹ Howard Hughes Medical Institute Research Scholar.

² To whom requests for reprints should be addressed at: Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20897.

Received 6/ 7/89. Revised 1/31/89. Revised 4/12/89. Accepted 4/19/89.

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