Optimal scheduling of interleukin 12 and chemotherapy in the murine MB-49 bladder carcinoma and B16 melanoma.
The antitumor activity of interleukin (IL)-12, a naturally occurring cytokine, has been demonstrated in several murine solid tumors. Animals bearing established B16 melanoma or MB-49 bladder carcinoma were used to study the most effective scheduling of recombinant murine IL-12 (rmIL-12), along with systemic chemotherapy. rmIL-12 (0. 45, 4.5, or 45 microgram/kg) was more effective as a single agent when administered to mice bearing the MB-49 bladder carcinoma at the highest dose for 11 doses rather than for 5 doses. In combination with chemotherapy (Adriamycin, cyclophosphamide, or 5-fluorouracil), rmIL-12 administration did not increase the toxicity of the chemotherapy, and there was increased antitumor activity with each rmIL-12-drug combination. Administering rmIL-12 (45 microgram/kg) on days 4-14, along with Adriamycin, cyclophosphamide, or 5-fluorouracil on days 7-11, resulted in 2.2-2.7-fold increases in tumor growth delay, compared with the chemotherapy alone against the primary tumor, and a marked decrease in the number of lung metastases on day 20. Because the B16 melanoma grows more slowly than the MB-49 bladder carcinoma, allowing multiple courses of chemotherapy, cyclophosphamide could be administered. The rmIL-12 (45 microgram/kg)-cyclophosphamide combination regimen that was most effective overlapped 2 days with the terminal portion of the chemotherapy treatment. There was a parallel increase in the response of the primary tumor and metastatic disease to the lungs. Administration of rmIL-12 to animals bearing the MB-49 bladder carcinoma or the B16 melanoma was compatible with coadministration of chemotherapy at full dose without additional toxicity.
Teicher
B A
BA
Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, MA 02115, USA.
Ara
G
G
Buxton
D
D
Leonard
J
J
Schaub
R G
RG
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000627:therapeutic use / Q000633:toxicity; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity; D004334:Drug Administration Schedule; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity; D007155:Immunologic Factors / Q000008:administration & dosage* / Q000627:therapeutic use; D018664:Interleukin-12 / Q000008:administration & dosage* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000628:therapy*
D007155:Immunologic Factors; D011994:Recombinant Proteins; D018664:Interleukin-12; D004317:Doxorubicin; D003520:Cyclophosphamide; D005472:Fluorouracil