title: Maximum tolerable doses of intravenous zidovudine in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer patients. Clinical evidence of significant antitumor activity and enhancement of zidovudine-induced DNA single strand breaks in peripheral nuclear blood cells.
abstract: BACKGROUND
  Experimental studies have demonstrated that 5-fluorouracil (5-FU) enhances zidovudine (AZT)-induced DNA strand breaks and cytotoxicity. Phase I studies have demonstrated that the maximum tolerable dose (MTD) of AZT is 8000 mg/sqm when administered i.v. over two hours after weekly 5-FU + l-leucovorin (LV), and that this combination has promising antitumor activity. The purpose of this study was therefore to evaluate the antitumor activity of weekly bolus 5-FU + LV + AZT, administered at its MTD, and to determine whether 5-FU enhances AZT-induced DNA strand breaks in blood nuclear cells.
  
  
  METHODS
  Twenty-nine chemotherapy-naïve metastatic colorectal cancer patients with measurable disease entered the study to evaluate the activity of a weekly 5-FU 500 mg/m2 i.v. bolus + LV 250 mg/m2 i.v. two-hour infusion + AZT 8000 mg/m2 i.v. two-hour infusion. In 10 different patients, who during three different weeks received 5-FU + LV, AZT and 5-FU + LV + AZT, DNA strand breaks in blood nuclear cells were determined by a fluorescent analysis of DNA unwinding.
  
  
  RESULTS
  Treatment was generally well tolerated and WHO grades III-IV toxicities, consisting mostly of diarrhea (17%), were uncommon. One patient died of severe diarrhea with consequent hypokalemia and cardiac arrhythmia. All patients were considered evaluable for response, and 3 (10%) complete and 10 (35%) partial responses were observed, for an objective response rate of 45% (95% confidence limit interval 26%-64%). Both 5-FU + LV and AZT decreased the percentage of double stranded DNA in nuclear blood cells. The greatest effect was observed with 5-FU + LV + AZT, which reduced the percentage of double stranded DNA to 50% and 36% after 24 and 48 hours, respectively, and this interaction between 5-FU + LV and AZT was found to be cumulative.
  
  
  CONCLUSIONS
  These studies demonstrate that the present dose and schedule of AZT in combination with 5-FU + LV has significant activity in metastatic colorectal cancer and that the combination of 5-FU + LV with AZT increases the amount of DNA damage. Therefore, AZT in combination with 5-FU + LV warrants further study in colorectal cancer.
authors.affiliation: U.O. Oncologia Medica, Ospedale S. Chiara, Pisa, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Falcone
authors.forename: M
authors.initials: M
authors.lastname: Lencioni
authors.forename: I
authors.initials: I
authors.lastname: Brunetti
authors.forename: E
authors.initials: E
authors.lastname: Pfanner
authors.forename: G
authors.initials: G
authors.lastname: Allegrini
authors.forename: A
authors.initials: A
authors.lastname: Antonuzzo
authors.forename: M
authors.initials: M
authors.lastname: Andreuccetti
authors.forename: G
authors.initials: G
authors.lastname: Malvaldi
authors.forename: R
authors.initials: R
authors.lastname: Danesi
authors.forename: M
authors.initials: M
authors.lastname: Del Tacca
authors.forename: P F
authors.initials: PF
authors.lastname: Conte
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000097:blood* / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000097:blood / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007275:Injections, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015215:Zidovudine / Q000008:administration & dosage
chemical_list: D004273:DNA, Neoplasm; D004277:DNA, Single-Stranded; D015215:Zidovudine; D002955:Leucovorin; D005472:Fluorouracil