Augmentation of antitumor efficacy by the combination of recombinant tumor necrosis factor and chemotherapeutic agents in vivo.
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 micrograms/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 micrograms of rhTNF and Cy (on Day 12) had tumor size reductions of 70 and 94%, respectively, compared to untreated controls (P2 less than 0.005). Mice treated with Cy alone, or with 4 or 6 micrograms of rhTNF alone had tumor size reductions of 30, 35, and 41%, respectively, compared to untreated controls (P2 less than 0.02). Analysis of cure rates demonstrates that the combination of Cy with 4 or 6 micrograms tumor necrosis factor cured 35 and 48% of the animals, respectively (P2 less than 0.01), compared to 10, 0, and 14% of mice treated with single agent Cy, 4 micrograms rhTNF, or 6 micrograms 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 less than 0.05) on Day 28 following tumor inoculation and none were cured. In contrast, mice treated with doxorubicin plus 4 or 6 micrograms rhTNF exhibited early reductions in tumor size such that on Day 28 the average tumor areas were decreased by 66 +/- 34% (P2 less than 0.05) and 73 +/- 1% (P2 less than 0.02) of untreated controls with cure rates of 29% and 43% (P2 less than 0.02), respectively. However, the combination of 6 micrograms 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 less than 0.05) over that of untreated controls on Day 28 following tumor inoculation.(ABSTRACT TRUNCATED AT 400 WORDS)
Krosnick
J A
JA
Surgery Branch, National Cancer Institute, Bethesda, Maryland 20892.
Mulé
J J
JJ
McIntosh
J K
JK
Rosenberg
S A
SA
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use*; D004317:Doxorubicin / Q000008:administration & dosage / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000627:therapeutic use*; D008748:Methylcholanthrene; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage / Q000627:therapeutic use*
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D008748:Methylcholanthrene; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil