PMID- 8637027
OWN - NLM
STAT- MEDLINE
DCOM- 19960711
LR  - 20190512
IS  - 0027-8874 (Print)
IS  - 0027-8874 (Linking)
VI  - 88
IP  - 11
DP  - 1996 Jun 5
TI  - Cytotoxic effects of topotecan combined with various anticancer agents in human 
      cancer cell lines.
PG  - 734-41
AB  - BACKGROUND: Topotecan (TPT) is a topoisomerase I poison that exhibits 
      antineoplastic activity. Analysis of the cytotoxic effects of combinations of TPT 
      and other anticancer agents has been limited. PURPOSE: We assessed the cytotoxic 
      effects produced by combinations of TPT and other antineoplastic agents in 
      experiments involving multiple human cancer cell lines of diverse histologic 
      origins. METHODS: The cytotoxic effects of various antimetabolites (fluorouracil, 
      methotrexate, or cytarabine), antimicrotubule agents (vincristine or paclitaxel 
      [Taxol]), DNA alkylating agents (melphalan, bis[chloroethyl]nitrosourea [BCNU], 
      or 4-hydroperoxycyclophosphamide [4HC]), and a DNA-platinating agent (cisplatin), 
      alone and in combination with TPT, were measured in clonogenic (i.e., 
      colony-forming) assays. HCT8 ileocecal adenocarcinoma, A549 non-small-cell lung 
      carcinoma, NCI-H82ras(H) lung cancer, T98G glioblastoma, and MCF-7 breast cancer 
      cell lines were used in these assays. The data were analyzed by the median effect 
      method, primarily under the assumption that drug mechanisms of action were 
      mutually nonexclusive (i.e., completely independent of one another). For each 
      level of cytotoxicity (ranging from 5% to 95%), a drug combination index (CI) was 
      calculated. A CI less than 1 indicated synergy (i.e., the effect of the 
      combination was greater than that expected from the additive effects of the 
      component agents), a CI equal to 1 indicated additivity, and a CI greater than 1 
      indicated antagonism (the effect of the combination was less than that expected 
      from the additive effects of the component agents). RESULTS: When the mechanisms 
      of drug action were assumed to be mutually nonexclusive, virtually all CIs for 
      combinations of TPT and either antimetabolites or antimicrotubule agents revealed 
      cytotoxic effects that were less than additive. The CIs calculated at 
      low-to-intermediate levels of cytotoxicity for combinations of TPT and the DNA 
      alkylating agents melphalan, BCNU, and 4HC also showed drug effects that were 
      less than additive; in most cases, however, nearly additive or even synergistic 
      effects were observed with these same drug combinations at high levels of 
      cytotoxicity (i.e., at > or = 90% inhibition of colony formation). Results 
      obtained with combinations of TPT and cisplatin varied according to the cell line 
      examined. With A549 cells, less than additive effects were seen at 
      low-to-intermediate levels of cytotoxicity, and more than additive effects were 
      seen at high levels of cytotoxicity. With NCI-H82ras(H) cells, synergy was 
      observed over most of the cytotoxicity range. CONCLUSIONS AND IMPLICATIONS: TPT 
      cytotoxicity appears to be enhanced more by combination with certain DNA-damaging 
      agents than by combination with antimetabolites or antimicrotubule agents. 
      Interactions between TPT and other drugs can vary depending on the cell type 
      examined. Further investigation is required to determine the basis of the 
      observed effects and to determine whether these in vitro findings are predictive 
      of results obtained in vivo.
FAU - Kaufmann, S H
AU  - Kaufmann SH
AD  - Division of Oncology Research, Mayo Clinic, Rochester, MN 55905, USA.
FAU - Peereboom, D
AU  - Peereboom D
FAU - Buckwalter, C A
AU  - Buckwalter CA
FAU - Svingen, P A
AU  - Svingen PA
FAU - Grochow, L B
AU  - Grochow LB
FAU - Donehower, R C
AU  - Donehower RC
FAU - Rowinsky, E K
AU  - Rowinsky EK
LA  - eng
GR  - CA66084/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Natl Cancer Inst
JT  - Journal of the National Cancer Institute
JID - 7503089
RN  - 0 (Antimetabolites, Antineoplastic)
RN  - 0 (Antineoplastic Agents, Alkylating)
RN  - 7M7YKX2N15 (Topotecan)
RN  - Q20Q21Q62J (Cisplatin)
RN  - XT3Z54Z28A (Camptothecin)
SB  - IM
CIN - J Natl Cancer Inst. 1996 Jun 5;88(11):699-700. PMID: 8637018
MH  - Antimetabolites, Antineoplastic/administration & dosage
MH  - Antineoplastic Agents, Alkylating/administration & dosage
MH  - Antineoplastic Combined Chemotherapy Protocols/*pharmacology
MH  - Camptothecin/administration & dosage/*analogs & derivatives
MH  - Cisplatin/administration & dosage
MH  - Drug Synergism
MH  - Humans
MH  - Microtubules/drug effects
MH  - Topotecan
MH  - Tumor Cells, Cultured
EDAT- 1996/06/05 00:00
MHDA- 1996/06/05 00:01
CRDT- 1996/06/05 00:00
PHST- 1996/06/05 00:00 [pubmed]
PHST- 1996/06/05 00:01 [medline]
PHST- 1996/06/05 00:00 [entrez]
AID - 10.1093/jnci/88.11.734 [doi]
PST - ppublish
SO  - J Natl Cancer Inst. 1996 Jun 5;88(11):734-41. doi: 10.1093/jnci/88.11.734.