Tumor resistance to alkylating agents conferred by mechanisms operative only in vivo
Abstract
EMT-6 murine mammary tumors were made resistant to cis-diamminedichloroplatinum (II) (CDDP), carboplatin, cyclophosphamide (CTX), or thiotepa in vivo by treatment of tumor-bearing animals with the drug during a 6-month period. In spite of high levels of in vivo resistance, no significant resistance was observed when the cells from these tumors were exposed to the drugs in vitro. The pharmacokinetics of CDDP and CTX were altered in animals bearing the respective resistant tumors. The resistance of all tumor lines except for the EMT-6/thiotepa decreased during 3 to 6 months in vivo passage in the absence of drugs. These results indicate that very high levels of resistance to anticancer drugs can develop through mechanisms that are expressed only in vivo.
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In vivo studies demonstrated that tumors exposed to repeated alkylating agent treatment in murine models developed significant resistance, which was not observed when the same cells were cultured in vitro, underscoring the essential role of stromal interactions in modulating therapeutic response.
“In vivo studies have demonstrated that tumors exposed to repeated alkylating agent treatment in murine models developed significant resistance, which was not observed when the same cells were cultured in vitro, underscoring the essential role of stromal interactions in modulating therapeutic response [146].”
From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [146]
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References 39 · Cited by 327
- Authors
- Teicher, B., Herman, T., Holden, S., Wang, Y., Pfeffer, M., Crawford, J., & Frei, E.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Venue
- Science
- Published
- 1990-03-23
- Volume
- 247
- Issue
- 4949
- Pages
- 1457-1461
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W1983075270
- Cited by
- 327
- References
- 39
- Citations by year
- 2026: 2 · 2025: 5 · 2023: 5 · 2022: 5 · 2021: 2 · 2020: 6 · 2019: 7 · 2018: 9 · 2017: 14 · 2016: 11 · 2015: 10 · 2014: 13 · 2013: 8 · 2012: 10
- FWCI
- 6.52
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (1p01ca038497-01)
- National Cancer Institute (P01-CA 38497)
- Topics
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Keywords
- alkylating agent resistance, cisplatin resistance, carboplatin, cyclophosphamide, thiotepa, pharmacokinetics, tumor-bearing animals, drug resistance reversal
- MeSH terms
- Alkylating Agents, Animals, Antineoplastic Agents, Cisplatin, Cyclophosphamide, Drug Resistance, Kidney, Liver, Mammary Neoplasms, Experimental, Mice, Inbred BALB C, Organoplatinum Compounds, Sulfhydryl Compounds, Thiotepa, Tissue Distribution, Tumor Cells, Cultured, Carboplatin, Mice
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