title: Tumor size and origin determine the antitumor activity of cisplatin or 5-fluorouracil and its modulation by leucovorin in murine colon carcinomas.
abstract: 5-Fluorouracil (FUra) is one of the few effective agents in the treatment of patients with colorectal cancer. Its effects on the target enzyme thymidylate synthase (TS) can be modulated by leucovorin (LV) or cisplatin (CDDP). Tumor size and differentiation of tumor characteristics can influence therapeutic efficacy. We therefore studied the relationship between tumor size (cutoff point 200 mm3) and the antitumor activity of FUra and its modulation by LV in murine Colon 26 and Colon 38 tumors. The doubling time of tumors measuring > 200 mm3 was about 160% longer. The antitumor effect of FUra in these large tumors was decreased and could not be modulated by LV. In addition, three subtypes of Colon 26 (Colon 26-A, Colon 26-B, and Colon 26-10) were identified and characterized for tumor-induced weight loss, TS activity, response to chemotherapy, and histological features. Mice bearing Colon 38 and Colon 26-10 did not lose weight as a result of tumor growth. Colon 26-A caused a weight loss of up to 19%, whereas mice with Colon 26-B tumors remained within 10% of their initial weight and tolerated at least 2.5 times more tumor load than did mice bearing Colon 26-A, which induces cachexia. Among untreated tumors, TS catalytic activity was highest in Colon 26-B (5536 pmol mg protein(-1) h(-1)) and lowest in Colon 38 (799 pmol mg protein(-1) h(-1)); Colon 26-A and Colon 26-10 had intermediate activities (about 2500 pmol mg protein(-1) h(-1)). 5-Fluoro-2'-deoxyuridine monophosphate (FdUMP) binding was comparable in the three Colon 26 subtypes but was lower in Colon 38. The antitumor activity of FUra could be modulated by LV in Colon 38, Colon 26-10, and Colon 26-A but could not in Colon 26-B, with complete responses (CR) being obtained in Colon 26-10 and Colon 38. The latter two were highly sensitive to CDDP, followed by Colon 26-A and Colon 26-B (CRs: 50%, 40%, 25%, and 0, respectively). Furthermore, necrosis was noted in Colon 26-B and Colon 38 but not in Colon 26-A. In conclusion, (1) the antitumor activity of FUra in large tumors is decreased and cannot be modulated by LV and (2) characteristics and sensitivity to chemotherapeutics can vary substantially in closely related tumors of the same origin.
authors.affiliation: Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
authors.forename: J A
authors.initials: JA
authors.lastname: Van Laar
authors.forename: Y M
authors.initials: YM
authors.lastname: Rustum
authors.forename: C L
authors.initials: CL
authors.lastname: Van der Wilt
authors.forename: K
authors.initials: K
authors.lastname: Smid
authors.forename: C M
authors.initials: CM
authors.lastname: Kuiper
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
authors.forename: G J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000230:Adenocarcinoma / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004347:Drug Interactions; D005260:Female; D005468:Fluorodeoxyuridylate / Q000378:metabolism; D005472:Fluorouracil / Q000627:therapeutic use*; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D002955:Leucovorin / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000931:Antidotes; D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D005468:Fluorodeoxyuridylate; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil