A comparative analysis of low-dose metronomic cyclophosphamide reveals absent or low-grade toxicity on tissues highly sensitive to the toxic effects of maximum tolerated dose regimens

被引:110
作者
Emmenegger, U
Man, S
Shaked, Y
Francia, G
Wong, JW
Hicklin, DJ
Kerbel, RS
机构
[1] Univ Toronto, Hlth Sci Ctr, Sunnybrook & Womens Coll, Dept Med Biophys, Toronto, ON M4N 3M5, Canada
[2] Univ Toronto, Sunnybrook Reg Canc Ctr, Sunnybrook & Womens Coll Hlth Sci Ctr, Dept Pathol Anat, Toronto, ON, Canada
[3] ImClone Syst Inc, New York, NY USA
关键词
D O I
10.1158/0008-5472.CAN-04-0580
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The survival benefits of traditional maximum tolerated dose (MTD) cytotoxic therapy have been modest for the treatment of most types of metastatic malignancy and, moreover, often come with increased acute and chronic toxicity. Recent studies have demonstrated that the frequent administration of comparatively low doses of cytotoxic agents, with no extended breaks [low-dose metronomic (LDM) chemotherapy], may not only be at least as efficient as MTD therapy but also less toxic. This coincides with an apparent selectivity for "activated" endothelial cells of the tumor vasculature. However, the impact of LDM chemotherapy on the most sensitive target cell populations normally affected by MTD therapy (i.e., bone marrow progenitors, gut mucosa, and hair follicle cells) has not been analyzed in experimental detail. Therefore, we compared effects of LDM and MTD cyclophosphamide (CTX) on bone marrow and gut mucosa. Furthermore, we studied the potential impact of LDM CTX on angiogenesis in the context of wound healing and evidence of organ toxicity. We show absent or moderate hematologic and intestinal toxicity of LDM as opposed to MTD CTX. Of note was the finding of sustained lymphopenia, which is not unexpected given the use of CTX as immunosuppressive drug. There was no negative impact on wound healing or evidence of organ toxicity. LDM offers clear safety advantages over conventional MTD chemotherapy and therefore would appear to be ideal for long-term combination therapy with targeted antiangiogenic drugs.
引用
收藏
页码:3994 / 4000
页数:7
相关论文
共 40 条
  • [1] Bertolini F, 2003, CANCER RES, V63, P4342
  • [2] Immunohistochemical detection of cell growth fraction in formalin-fixed and paraffin-embedded murine tissue
    Birner, P
    Ritzi, M
    Musahl, C
    Knippers, P
    Gerdes, J
    Voigtländer, T
    Budka, H
    Hainfellner, JA
    [J]. AMERICAN JOURNAL OF PATHOLOGY, 2001, 158 (06) : 1991 - 1996
  • [3] Blumenthal RD, 2002, CLIN CANCER RES, V8, P1301
  • [4] Thrombospondin 1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy
    Bocci, G
    Francia, G
    Man, S
    Lawler, J
    Kerbel, RS
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (22) : 12917 - 12922
  • [5] Bocci G, 2002, CANCER RES, V62, P6938
  • [6] Browder T, 2000, CANCER RES, V60, P1878
  • [7] Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of intergroup trial C9741/cancer and leukemia group B trial 9741
    Citron, ML
    Berry, DA
    Cirrincione, C
    Hudis, C
    Winer, EP
    Gradishar, WJ
    Davidson, NE
    Martino, S
    Livingston, R
    Ingle, JN
    Perez, EA
    Carpenter, J
    Hurd, D
    Holland, JF
    Smith, BL
    Sartor, CI
    Leung, EH
    Abrams, J
    Schilsky, RL
    Muss, HB
    Norton, L
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 2003, 21 (08) : 1431 - 1439
  • [8] Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer:: antitumor activity and correlation with vascular endothelial growth factor levels
    Colleoni, M
    Rocca, A
    Sandri, MT
    Zorzino, L
    Masci, G
    Nolè, F
    Peruzzotti, G
    Robertson, C
    Orlando, L
    Cinieri, S
    de Braud, F
    Viale, G
    Goldhirsch, A
    [J]. ANNALS OF ONCOLOGY, 2002, 13 (01) : 73 - 80
  • [9] Oral chemotherapy: Rationale and future directions
    DeMario, MD
    Ratain, MJ
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 1998, 16 (07) : 2557 - 2567
  • [10] DOUAY L, 1989, EXP HEMATOL, V17, P429