Purpose
We assessed the combination of doxorubicin or liposomal doxorubicin with trastuzumab for alterations in peak serum drug levels, as these agents are increasingly being paired in the treatment of aggressive breast cancer. We hypothesized that trastuzumab would exhibit a slower rate of elimination from the serum when in combination with liposomal doxorubicin based on the known effects of liposomal doxorubicin on phagocytic cells of the mononuclear phagocyte system (MPS), which are responsible in part for the uptake and degradation of antibodies.
Methods
Doxorubicin and trastuzumab serum levels were assessed following injection of free doxorubicin, liposomal doxorubicin, or trastuzumab into female RAG2-M mice bearing subcutaneous MCF-7HER-2 tumors. The effects of combination drug treatment on tumor growth were compared to single-agent treatment.
Results
Peak serum trastuzumab levels were not altered as a result of addition of doxorubicin therapy, nor were doxorubicin levels altered over 24 h as a result of coadministration of trastuzumab. Liposomal doxorubicin administration did result in serum doxorubicin levels 200- to 1000-fold higher than with injection of free doxorubicin.
Conclusions
For the specific combination of trastuzumab with doxorubicin, either in free or liposomal form, coadministered in mice, there was no impact of one drug on the other in terms of peak serum drug levels or efficacy.
Similar content being viewed by others
Abbreviations
- AC:
-
doxorubicin and cyclophosphamide
- AUC:
-
area under the curve
- i.p.:
-
intraperitoneal
- PBS:
-
phosphate-buffered saline
- TMB:
-
tetramethylbenzidine
References
J. H. Goldie (1989) ArticleTitleNew information on drug resistance: implications for the adjuvant treatment of breast cancer Recent Results Cancer Res. 115 8–16 Occurrence Handle1:STN:280:By%2BC287ltVw%3D Occurrence Handle2696044
E. Frei SuffixIII (1984) ArticleTitleAcute leukemia in children. Model for the development of scientific methodology for clinical therapeutic research in cancer Cancer 53 2013–2025 Occurrence Handle6367931
M. H. Beers (Eds) (2003) Merck Manual of Medical Information Merck Research Laboratories Whitehouse Station, NJ
J. H. Lin (2003) ArticleTitleDrug–drug interaction mediated by inhibition and induction of P-glycoprotein Adv. Drug Deliv. Rev. 55 53–81 Occurrence Handle1:CAS:528:DC%2BD3sXivVWntw%3D%3D Occurrence Handle12535574
D. Lopes L. D. Mayer (2002) ArticleTitlePharmacokinetics of Bcl-2 antisense oligonucleotide (G3139) combined with doxorubicin in SCID mice bearing human breast cancer solid tumor xenografts Cancer Chemother. Pharmacol. 49 57–68 Occurrence Handle11855753
H. Wang M. Li J. J. Rinehart R. Zhang (2004) ArticleTitleDexamethasone as a chemoprotectant in cancer chemotherapy: hematoprotective effects and altered pharmacokinetics and tissue distribution of carboplatin and gemcitabine Cancer Chemother. Pharmacol. 53 459–467 Occurrence Handle1:CAS:528:DC%2BD2cXjvVKhtLk%3D Occurrence Handle14752578
A. C. Wolff M. Bonetti J. A. Sparano (2003) ArticleTitleCardiac safety of trastuzumab (H) in combination with pegylated liposomal doxorubicin (D) and docetaxel (T) in HER2-positive metastatic breast cancer (MBC): preliminary results of the Eastern Cooperative Oncology Group trial E3198 Proc. Am. Soc. Clin. Oncol. 22 A-70
M. A. Rodriguez, A. Sarris, K. East, N. H. Dang, L. Fayad, A. Goy, F. Hagemeister, B. Pro, J. Romaguera, F. Samaniego, A. Younes, and F. Cabanillas. A phase II study of liposomal vincristine in CHOP with rituximab for elderly patients with untreated aggressive B-cell non-Hodgkin’s lymphoma (NHL). ASCO Gen. Meet. Abstract #1132 (2002).
F. Montemurro G. Valabrega M. Aglietta (2004) ArticleTitleTrastuzumab-based combination therapy for breast cancer Expert Opin. Pharmacother. 5 81–96 Occurrence Handle1:CAS:528:DC%2BD3sXpvVeqtbw%3D Occurrence Handle14680438
R. Repp H. H. Ojik Particlevan T. Valerius G. Groenewegen G. Wieland C. Oetzel B. Stockmeyer W. Becker M. Eisenhut H. Steininger Y. M. Deo G. H. Blijham J. R. Kalden J. G. Winkel Particlevan de M. Gramatzki (2003) ArticleTitlePhase I clinical trial of the bispecific antibody MDX-H210 (anti-FcgammaRI (anti-HER-2/neu) in combination with Filgrastim (G-CSF) for treatment of advanced breast cancer Br. J. Cancer 89 2234–2243 Occurrence Handle1:CAS:528:DC%2BD3sXpvVShtbo%3D Occurrence Handle14676800
B. Ramaswamy C. L. Shapiro (2003) ArticleTitlePhase II trial of bevacizumab in combination with docetaxel in women with advanced breast cancer Clin. Breast Cancer 4 292–294 Occurrence Handle1:CAS:528:DC%2BD3sXpvF2gtb8%3D Occurrence Handle14651775
L. M. Weiner (1999) ArticleTitleMonoclonal antibody therapy of cancer Semin. Oncol. 26 43–51 Occurrence Handle1:CAS:528:DyaK1MXnslGjtrc%3D
M. Mehren Particlevon G. P. Adams L. M. Weiner (2003) ArticleTitleMonoclonal antibody therapy for cancer Ann. Rev. Cancer 54 343–369
B. Gatto (2004) ArticleTitleMonoclonal antibodies in cancer therapy Curr. Med. Ther.–Anti-Cancer Agents 4 411–414 Occurrence Handle1:CAS:528:DC%2BD2cXntVertb4%3D
D. J. Slamon B. Leyland-Jones S. Shak H. Fuchs V. Paton A. Bajamonde T. Fleming W. Eiermann J. Wolter M. Pegram J. Baselga L. Norton (2001) ArticleTitleUse of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N. Engl. J. Med. 344 783–792 Occurrence Handle1:CAS:528:DC%2BD3MXisVGktrc%3D Occurrence Handle11248153
L. A. Emens N. E. Davidson (2004) ArticleTitleTrastuzumab in breast cancer Oncology 18 1117–1128 Occurrence Handle15471197
R. Bell S. Verma M. Untch D. Cameron I. Smith (2004) ArticleTitleMaximizing clinical benefit with trastuzumab Semin. Oncol. 31 35–44 Occurrence Handle1:CAS:528:DC%2BD2cXhtVSlu7zM
M. A. Cobeigh, C. L. Vogel, D. Tripathy, N. J. Robert, S. Scholl, L. Fehrenbacher, V. Paton, S. Shak, G. Lieberman, and D. Slamon. Efficacy and safety of Herceptin (humanized anti-HER2 antibody) as a single agent in 222 women with HER2 overexpression who relapsed following chemotherapy for metastatic breast cancer. Proc. Am. Soc. Clin. Oncol. Abstract #376 (1998).
D. C. Allred A. K. Tandon G. M. Clark W. L. McGuire (1991) Her2/neu oncogene amplification and expression in human mammary carcinoma T. G. Pretlow SuffixII T. P. Pretlow (Eds) Biochemical and Molecular Aspects of Selected Cancers, Vol. 1 Academic Press, Inc. San Diego, CA, USA; London, England, UK 75–97
A. Berchuck A. Kamel R. Whitaker B. Kerns G. Olt R. Kinney J. T. Soper R. Dodge D. L. Clarke-Pearson P. Marks (1990) ArticleTitleOverexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer Cancer Res. 50 4087–4091 Occurrence Handle1:STN:280:By%2BB1czptVU%3D Occurrence Handle1972347
W. B. Carter J. B. Hoying C. Boswell S. K. Williams (2001) ArticleTitleHER2/neu over-expression induces endothelial cell retraction Int. J. Cancer 91 295–299 Occurrence Handle1:CAS:528:DC%2BD3MXmsFOkuw%3D%3D Occurrence Handle11169950
A. Harlozinska J. K. Bar R. Wenderski M. Bebenek (1996) ArticleTitleRelationship between c-erbB-2 oncoprotein, epidermal growth factor receptor, and estrogen receptor expression in patients with ductal breast carcinoma. Association with tumor phenotypes In vivo 10 217–222 Occurrence Handle1:CAS:528:DyaK28XjvFygsrk%3D Occurrence Handle8744803
A. H. McCann P. A. Dervan M. O’Regan M. B. Codd W. J. Gullick B. M. J. Tobin D. N. Carney (1991) ArticleTitlePrognostic significance of c-erbB-2 and estrogen receptor status in human breast cancer Cancer Res. 51 3296–3303 Occurrence Handle1:STN:280:By6B2cbjsFE%3D Occurrence Handle1674898
M. Piccart C. Lohrisch A. Leo ParticleDi D. Larsimont (2001) ArticleTitleThe predictive value of Her-2 in breast cancer Oncology 61 73–82 Occurrence Handle1:CAS:528:DC%2BD3MXovFWjsb4%3D Occurrence Handle11694791
D. J. Slamon W. Godolphin L. A. Jones J. A. Holt S. G. Wong D. E. Keith W. J. Levin S. G. Stuart J. Udove A. Ullrich M. A. Press (1989) ArticleTitleStudies of HER-2/neu proto-oncogene in human breast and ovarian cancer Science 244 707–712 Occurrence Handle1:STN:280:BiaB2c3hsVA%3D Occurrence Handle2470152
J. A. Kern D. A. Schwartz J. E. Nordberg D. B. Weiner M. I. Greene L. Torney R. A. Robinson (1990) ArticleTitleP185neu expression in human lung adenocarcinomas predicts shortened survival Cancer Res. 50 5184–5187 Occurrence Handle1:CAS:528:DyaK3cXls12ltr4%3D Occurrence Handle1974168
M.-C. Hung Y.-K. Lau (1999) ArticleTitleBasic Science of HER-2/neu: a review Semin. Oncol. 26 51–59 Occurrence Handle1:CAS:528:DyaK1MXmt1Sisbk%3D
Y. Wen M.C.-T. Hu K. Makino B. Spohn G. Bartholomeusz D.-H. Yan M.-C. Hung (2000) ArticleTitleHer-2/neu promotes androgen-independent survival and growth of prostate cancer cells through the Akt pathway Cancer Res. 60 6841–6845 Occurrence Handle1:CAS:528:DC%2BD3MXjsVKrtQ%3D%3D Occurrence Handle11156376
C. Ensinger R. Kremser P. Obrist D. Kendler H. Erler (2002) ArticleTitleHer2/neu overexpression in differentiated thyroid carcinomas Proc. AACR 43 717
S. U. Goebel M. Iwamoto M. Raffeld F. Gibril W. Hou J. Serrano R. T. Jensen (2002) ArticleTitleHer-2/neu expression and gene amplification in gastriomas: correlations with tumor biology, growth, and aggressiveness Cancer Res. 62 3702–3710 Occurrence Handle1:CAS:528:DC%2BD38XltF2jtb8%3D Occurrence Handle12097278
A. D. Santin S. Bellone M. Palmieri M. Gokden J. J. Roman S. Pecorelli M. J. Cannon L. F. Hutchins J. G. Agha D. L. Dunn T. J. O’Brien P. P. Groesbeck (2002) ArticleTitleHER2/neu overexpression in uterine serous papillary cancer Proc. AACR 43 716–717
M. Fornier P. Munster A. D. Seidman (1999) ArticleTitleUpdate on the management of advanced breast cancer Oncology 13 647–664 Occurrence Handle1:STN:280:DyaK1M3osFWksQ%3D%3D Occurrence Handle10356685
D. J. Slamon B. Leyland-Jones S. Shak H. Fuchs V. Paton A. Bajamonde T. Fleming W. Eiermann J. Wolter M. Pegram J. Baselga L. Norton (2001) ArticleTitleUse of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2 N. Engl. J. Med. 344 783–792 Occurrence Handle1:CAS:528:DC%2BD3MXisVGktrc%3D Occurrence Handle11248153
S. Gori M. Colozza A. M. Mosconi E. Franceschi C. Basurto R. Cherubini A. Sidoni A. Rulli C. Bisacci V. Angelis ParticleDe L. Crino M. Tonato (2004) ArticleTitlePhase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer Br. J. Cancer 90 36–40 Occurrence Handle1:CAS:528:DC%2BD2cXhtFKntQ%3D%3D Occurrence Handle14710203
S. Stein A. DeMichele S. Domchek K. Fox (2004) ArticleTitleGemcitabine and trastuzumab combinations for patients with metastatic breast cancer overexpressing HER2/neu Clin. Breast Cancer 4 S117–S120 Occurrence Handle1:CAS:528:DC%2BD2cXitlymsrk%3D Occurrence Handle14754469
F. Montemurro G. Choa R. Faggiuolo M. Donadio M. Minischetti A. Durando A. Capaldi G. Vietti-Ramus O. Alabiso M. Aglietta (2004) ArticleTitleA phase II study of three-weekly docetaxel and weekly trastuzumab in HER2-overexpressing advanced breast cancer Oncology 66 38–45 Occurrence Handle1:CAS:528:DC%2BD2cXitlyitLg%3D Occurrence Handle15031597
M. S. Ewer H. R. Gibbs J. Swafford R. S. Benjamin (1999) ArticleTitleCardiotoxicity in patients receiving transtuzumab (Herceptin): primary toxicity, synergistic or sequential stress, or surveillance artifact? Semin. Oncol. 26 96–101 Occurrence Handle1:CAS:528:DyaK1MXmt1Sitrw%3D Occurrence Handle10482200
S. K. Rigatos D. Tsavdraris A. Athanasiadis J. G. Stathopoulos G. P. Stathopoulos (2003) ArticleTitlePaclitaxel and liposomal doxorubicin (Caelyx) combination in advanced breast cancer patients: a phase II study Oncol. Rep. 10 1817–1819 Occurrence Handle1:CAS:528:DC%2BD3sXptlCktbk%3D Occurrence Handle14534702
T. Safra (2003) ArticleTitleCardiac safety of liposomal anthracyclines The Oncologist 8 17–24 Occurrence Handle1:CAS:528:DC%2BD3sXotF2qt7g%3D Occurrence Handle13679592
M. E. O’Brein N. Wigler M. Inbar R. Rosso E. Grischke A. Santoro R. Catane D. G. KIieback P. Tomczak S. P. Ackland F. Orlandi L. Mellars L. Alland C. Tendler InstitutionalAuthorNameCAELYX Breasts Cancer Study Group (2004) Ann. Oncol. 15 440–449 Occurrence Handle14998846
A. Gabizon R. Catane B. Uziely B. Kaufman T. Safra R. Cohen F. Martin (1994) ArticleTitleProlonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes Cancer Res. 54 987–992 Occurrence Handle1:CAS:528:DyaK2cXhslegs70%3D Occurrence Handle8313389
F. Muggia A. Hamilton (2001) ArticleTitlePhase III data on Caelyx in ovarian cancer Eur. J. Cancer 37 S15–S18 Occurrence Handle1:CAS:528:DC%2BD3MXptVShsr0%3D Occurrence Handle11741769
D. N. Waterhouse P. Tardi L. G. Mayer M. Bally (2001) ArticleTitleA comparison of liposomal formulations of doxorubicin with drug administered in free form Drug Safety 24 903–920 Occurrence Handle1:CAS:528:DC%2BD3MXptVyisrc%3D Occurrence Handle11735647
T. Daemen G. Hofstede M. T. Ten Kate I. A. Bakker-Woudenberg G. L. Scherphof (1995) ArticleTitleLiposomal doxorubicin-induced toxicity: depletion and impairment of phagocytic activity of liver macrophages Int. J. Cancer 61 716–721 Occurrence Handle1:CAS:528:DyaK2MXms1Smtb0%3D Occurrence Handle7768646
M. J. Parr S. M. Ansell L. S. Choi P. R. Cullis (1993) ArticleTitleThe presence of GM1 in liposomes with entrapped doxorubicin does not prevent RES blockade Biochim. Biophys. Acta 1168 249–252 Occurrence Handle1:CAS:528:DyaK3sXksFGqtLc%3D Occurrence Handle8504161
M. J. Parr D. Masin P. R. Cullis M. B. Bally (1997) ArticleTitleAccumulation of liposomal lipid and encapsulated doxorubicin in murine lewis lung carcinoma: the lack of beneficial effects by coating liposomes with poly(ethylene glycol) J. Pharmacol. Exp. Ther. 280 1319–1327 Occurrence Handle1:CAS:528:DyaK2sXhvF2mtbw%3D Occurrence Handle9067319
I. A. Bakker-Woudenberg (2002) ArticleTitleLong-circulating sterically stabilized liposomes as carriers of agents for treatment of infection or for imaging infectious foci Int. J. Antimicrob. Agents 19 299–311 Occurrence Handle1:CAS:528:DC%2BD38XjtVeisL0%3D Occurrence Handle11978501
E. D. Lobo R. J. Hansen J. P. Balthasar (2004) ArticleTitleAntibody pharmacokinetics and pharmacodynamics J. Pharm. Sci. 93 2645–2668 Occurrence Handle1:CAS:528:DC%2BD2cXpvV2isLk%3D Occurrence Handle15389672
M. Pegram S. Hsu G. Lewis R. Pietras M. Beryt M. Sliwkowski D. Coombs D. Baly F. Kabbinavar D. Slamon (1999) ArticleTitleInhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers Oncogene 18 2241–2251 Occurrence Handle1:CAS:528:DyaK1MXis12murk%3D Occurrence Handle10327070
R. J. Pietras M. D. Pegram R. S. Finn D. A. Maneval D. J. Slamon (1998) ArticleTitleRemission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs Oncogene 17 2235–2249 Occurrence Handle1:CAS:528:DyaK1cXntlelu78%3D Occurrence Handle9811454
C. C. Benz K. G. Scott J. C. Sarup R. M. Johnson D. Tripathy E. Coronado E. M. Shepard C. K. Osborne (1993) ArticleTitleEstrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu Breast Cancer Res. Treat. 24 85–95 Occurrence Handle1:CAS:528:DyaK3sXitVCrsrg%3D Occurrence Handle8095168
S. Palm R. M. Enmon SuffixJr. C. Matei K. S. Kolbert S. Xu P. B. Zanzonico R. L. Finn J. A. Koutcher S. M. Larson G. Sgouros (2003) ArticleTitlePharmacokinetics and biodistribution of (86)Y-trastuzumab for (90)Y dosimetry in an ovarian carcinoma model: correlative microPET and MRI J. Nucl. Med. 44 1148–1155 Occurrence Handle1:CAS:528:DC%2BD3sXmtF2msbg%3D Occurrence Handle12843231
L. Embree K. A. Gelmon A. Lohr L. D. Mayer A. J. Coldman P. R. Cullis W. Palaitis F. Pilkiewicz N. J. Hudon J. R. Heggie J. H. Goldie (1993) ArticleTitleChromatographic analysis and pharmacokinetics of liposome-encapsulated doxorubicin in non-small-cell lung cancer patients J. Pharm. Sci. 82 627–634 Occurrence Handle1:CAS:528:DyaK3sXksVSit7o%3D Occurrence Handle8392545
S. M. Shafie (1980) ArticleTitleEstrogen and the growth of breast cancer: new evidence suggests indirect action Science 209 701–702 Occurrence Handle1:CAS:528:DyaL3cXlt1Khsro%3D Occurrence Handle6994231
Drug–Drug Interactions: Studies in Vitro and in Vivo. Therapeutic Products Directorate, Health Canada. http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/drug_int_e.html (accessed 10/13/04).
Acknowledgments
D.N. Waterhouse was supported by a Postgraduate Fellowship from the Canadian Breast Cancer Foundation. M.B. Bally was supported by the National Cancer Institute of Canada.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Waterhouse, D.N., Denyssevych, T., Hudon, N. et al. Trastuzumab and Liposomal Doxorubicin in the Treatment of MCF-7 Xenograft Tumor-Bearing Mice: Combination Does Not Affect Drug Serum Levels. Pharm Res 22, 915–922 (2005). https://doi.org/10.1007/s11095-005-4586-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11095-005-4586-z