Influence of treatment sequence on efficacy of fluorouracil and cisplatin intratumoral drug delivery in vivo.
OBJECTIVE
The influence of treatment sequence in combination chemotherapy using fluorouracil (5-FU) and cisplatin (CDDP) was investigated in a mouse tumor model. Both drugs were formulated as therapeutic injectable gels, 5-FU/epinephrine gel and CDDP/epinephrine gel, and used intratumorally in a multiple-treatment regimen. By testing various multiple-treatment regimens, we determined optimal treatment sequences for these two injectable gels. Then we compared the antitumor responses achieved using the optimal treatment sequences for the intratumorally administered gels with the responses obtained using 5-FU and CDDP solutions administered intratumorally or systemically in the same treatment sequence.


METHODS
Tumor-bearing C3H mice received a total of four injections (every 2 to 3 days from day 0 through day 7) of 5-FU solution, CDDP solution, 5-FU/epinephrine gel, or CDDP/epinephrine gel either as single agents or in various combinations and alternate sequences of solutions or gels. The delay in tumor growth was used as a study end-point.


RESULTS
The results showed that local treatment (i.e., intratumoral administration) was more efficacious than systemic treatment (i.e., intraperitoneal administration) when both 5-FU solution and CDDP solution were used either alone or in combination. Further, using two drugs in combination was superior to using either drug alone. When both drugs were delivered intratumorally in the injectable gel formulations, the combination treatment sequences initiated with 5-FU/epinephrine gel were superior to sequences initiated with CDDP/epinephrine gel in delaying the tumor growth. The two sequences initiated with 5-FU/epinephrine gel (i.e., two treatments with 5-FU/epinephrine gel followed by two treatments with CDDP/epinephrine gel and the sequence of alternating 5-FU/epinephrine gel and CDDP/epinephrine gel) showed no significant difference in antitumor efficacy. Both these sequences (initiated with 5-FU/epinephrine gel) produced the longest delays in tumor growth, and > or = 50% (7 of 12) animals remained disease free at the end of the 60-day study.


CONCLUSIONS
These studies demonstrate that significant improvement in local tumor control in mice can be achieved with a simple treatment sequence alteration of two established drugs.
Yu
N Y
NY
Matrix Pharmaceutical, Inc., Menlo Park, CA 94025, USA.
Patawaran
M B
MB
Chen
J Y
JY
Orenberg
E K
EK
Brown
D M
DM
Luck
E E
EE
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy*; D002945:Cisplatin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004837:Epinephrine / Q000008:administration & dosage; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy*; D005472:Fluorouracil / Q000008:administration & dosage; D005782:Gels / Q000008:administration & dosage; D015552:Injections, Intralesional; D051379:Mice; D008809:Mice, Inbred C3H
D005782:Gels; D002945:Cisplatin; D005472:Fluorouracil; D004837:Epinephrine