title: Phase II study of sequentially administered low-dose mitomycin-C (MMC) and irinotecan (CPT-11) in women with metastatic breast cancer (MBC).
abstract: BACKGROUND
  Preclinical studies show that mitomycin-C (MMC) followed by irinotecan (CPT-11) is synergistic. Therefore, we evaluated the toxicity and efficacy of sequentially administered low-dose MMC and CPT-11 in patients (pts) with pretreated metastatic breast cancer (MBC). Secondary objective was to evaluate the correlation between MMC-induced topoisomerase I (TOPO I) expression and NAD(P)H:quinone oxireductase 1 (NQO1) genotypes in peripheral blood mononuclear cells (PBMC) and efficacy or toxicity of the regimen.
  
  
  METHODS
  Thirty-two pts received MMC i.v. 6 mg/m(2) day 1 and CPT-11 i.v. 125 mg/m(2) days 2 and 8 every 28 days for maximum of six cycles. TOPO I expression and NQO1 reductase genotyping in 23 of 32 (72%) pts were assayed by PCR.
  
  
  RESULTS
  The median time to progression (TTP) was 4.7 months (95% confidence interval 4.0-5.4 months). TOPO I expression was increased 5- to 10-fold and 20- to 30-fold in PBMC at 24 and 168 h, respectively. There was no relationship between these markers and efficacy or toxicity of the regimen.
  
  
  CONCLUSIONS
  Sequential low-dose MMC and CPT-11 was active and tolerable by pretreated MBC pts. Future trials should focus on less pretreated MBC pts and sequential tumor biopsies to test the hypothesis that increased intratumoral expression of TOPO I is related to efficacy.
authors.affiliation: Division of Hematology and Oncology, Ohio State University Medical Center, Columbus, Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing; Comprehensive Breast Health Services, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus. Electronic address: ewa.mrozek@osumc.edu.
authors.forename: E
authors.initials: E
authors.lastname: Mrozek
authors.affiliation: School of Pharmacy, University of Wisconsin, Madison.
authors.forename: J
authors.initials: J
authors.lastname: Kolesar
authors.affiliation: Center for Biostatistics, Comprehensive Cancer Center, The Ohio State University, Columbus.
authors.forename: D
authors.initials: D
authors.lastname: Young
authors.affiliation: Comprehensive Breast Health Services, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus; Clinical Trials Office, Comprehensive Cancer Center, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, USA.
authors.forename: J
authors.initials: J
authors.lastname: Allen
authors.affiliation: Division of Hematology and Oncology, Ohio State University Medical Center, Columbus, Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing.
authors.forename: M
authors.initials: M
authors.lastname: Villalona-Calero
authors.affiliation: Division of Hematology and Oncology, Ohio State University Medical Center, Columbus, Beijing Cancer Hospital and Institute, Peking University School of Oncology, Beijing; Comprehensive Breast Health Services, Ohio State University Medical Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus.
authors.forename: C L
authors.initials: CL
authors.lastname: Shapiro
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D004264:DNA Topoisomerases, Type I / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D006801:Humans; D000077146:Irinotecan; D007963:Leukocytes, Mononuclear / Q000201:enzymology; D008875:Middle Aged; D016685:Mitomycin / Q000008:administration & dosage / Q000009:adverse effects; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D009362:Neoplasm Metastasis; D020641:Polymorphism, Single Nucleotide
chemical_list: D016685:Mitomycin; D000077146:Irinotecan; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin