Mitomycin C and etoposide in advanced colorectal carcinoma. A clinical and in vitro experience that focuses the problem of schedule dependence in combination therapy.
BACKGROUND
Aim of this study was to evaluate the activity of a combination regimen of chemotherapy containing mitomycin C (MMC) and etoposide (ETO) in advanced colorectal carcinoma.


METHODS
Fourteen pretreated patients received MMC 2 mg/m2 and ETO 60 mg/m2, days 1-5 every 28 days. The clinical study was interrupted since no clinical response was observed in 14 patients following four courses of chemotherapy. An in vitro study was then performed on HTC-8 cell line. The cytotoxic activity of the MMC/ETO combination was tested by sulforhodamine B assay and the type of drug interaction was assessed using the method of Chou and Talalay. Cell cycle perturbations and apoptosis were evaluated by flow cytometry.


RESULTS
While MMC and ETO were singularly active, the simultaneous exposure of cells to both drugs and the sequence MMC-->ETO ensued in antagonistic interaction at all levels of killed cell fraction. Conversely, the sequence ETO-->MMC produced a synergistic interaction.


CONCLUSIONS
These results suggest that the activity of the MMC/ETO combination is highly schedule-dependent and that the experimental drug associations should be based on a preclinical rationale before clinical trials are designed.
Seminara
P
P
Department of Clinical Medicine, Chemotherapy Unit, University La Sapienza, Rome, Italy. Patsem@libero.it
Pastore
C
C
Iascone
C
C
Cicconetti
F
F
Nigita
G
G
Ielapi
T
T
Franchi
F
F
D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D016685:Mitomycin; D005047:Etoposide