Tumor Resistance to Alkylating Agents Conferred by Mechanisms Operative Only in Vivo

Teicher, Beverly A.; Herman, Terence S.; Holden, Sylvia A.; Wang, Yenyun; Pfeffer, M. Raphael; Crawford, J. Webb; Frei, Emil

doi:10.1126/science.2108497

Cited by 285 publications

(157 citation statements)

References 16 publications

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“…Tofilon et al 26 reported the enhancement of spontaneous metastasis of a hepatocarcinoma growing intramuscularly following administration of a single dose of BCNU. Teicher et al 27 established 4 alkylating agent-resistant variants of a murine mammary tumour cell line, EMT-6, in vivo by repeated treatment of tumour-bearing mice with CPT, carboplatin, cyclophosphamide or thiotepa. These drug-resistant cell lines (particularly the CPT-resistant variant) were much more efficient at forming spontaneous lung metastases after s.c. injection of cells in comparison to the drug-sensitive parental line.…”

Section: Discussionmentioning

confidence: 99%

“…These drug-resistant cell lines (particularly the CPT-resistant variant) were much more efficient at forming spontaneous lung metastases after s.c. injection of cells in comparison to the drug-sensitive parental line. 28,29 Using the method of Teicher et al, 27 Mitsumoto et al 30 established 2 CPTresistant mouse epithelial tumour cell lines with enhanced metastatic capabilities associated with higher levels of cell adhesion to ECM components, such as fibronectin, laminin, collagen type IV and Matrigel; enhanced MMP-2 activity; and higher levels of cell motility. Van Putten et al 31 showed that treatment of animals bearing a transplantable osteosarcoma with cyclophosphamide or CCNU resulted in a significant increase in lung metastases compared to controls.…”

Section: Discussionmentioning

confidence: 99%

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Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Liang

O’Driscoll

McDonnell

et al. 2004

Intl Journal of Cancer

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The human lung carcinoma cell line DLKP was exposed to sequential pulses of 10 commonly used chemotherapeutic drugs (VP-16, vincristine, taxotere, mitoxantrone, 5-fluorouracil, methotrexate, CCNU, BCNU, cisplatin and chlorambucil); resulting cell lines exhibited resistance to the selecting agents (ranging approx. 1.5-to 36-fold) and, in some cases, cross-resistance to methotrexate (approx. 1.4-to 22-fold), vincristine (1.6-to 262-fold), doxorubicin (Adriamycin, approx. 1.1-to 33-fold) and taxotere (approx. 1.1-to 36-fold). Several of the variants displayed collateral sensitivity to cisplatin. A marked increase in in vitro invasiveness and motility was observed with variants pulsed with mitoxantrone, 5-fluorouracil, methotrexate, BCNU, cisplatin and chlorambucil. There was no significant change in invasiveness of cells pulsed with VP-16, vincristine, taxotere or CCNU. All of the pulseselected variants showed elevated levels of MDR-1/P-gp protein by Western blot analysis, although mdr-1 mRNA levels were not increased (except for DLKP-taxotere). In DLKPtaxotere, MRP1 protein levels were also greatly elevated, but mrp1 mRNA levels remained unchanged. BCRP was upregulated in DLKP-mitoxantrone at both the mRNA and protein levels. Gelatin zymography, Western blot and RT-PCR showed that DLKP and its variants secreted MMPs 2, 9 and 13. MMP inhibition assays suggested that MMP-2 plays a more important role than MMPs 9 and 13 in cell invasion of these DLKP drug-resistant variants in vitro. Reducing intracellular drug levels, often associated with overexpression of P-gp, 3 members of the MRP family 4 and the BCRP/ MXR protein, 5 is an important and frequent mechanism of MDR.Invasion through basement membrane is believed to be a critical step in metastasis. There are 4 main classes of proteases involved in proteolytic degradation of the ECM: serine-, cysteine-and aspartyl-proteases as well as MMPs. 6 The MMPs are a family of more than 20 members produced by tumour cells, connective tissue cells and inflammatory cells. MMPs are secreted as latent proenzymes and activated by proteolytic removal of an aminoterminal domain. 7 A large body of evidence shows that MMPs play a crucial role in cancer invasion and metastasis. Based on sequence homology and substrate specificity, MMP-2 and MMP-9 are classified as type IV collagenases that degrade the major component (type IV collagen) of basement membrane; 8 MMP-13, also called "collagenase-3", belongs to a group known as interstitial collagenases, which degrade collagen types I, II, III, VII, VIII and X. 9 The possibility of a relationship between drug resistance and invasion/metastasis phenotypes has been raised by 2 types of observation: 10 firstly, some tumour cells selected for resistance to drugs are invasive/metastatic relative to nonresistant parental cells; secondly, in some cases, secondary (more metastatic) tumours are more resistant to chemotherapeutic drugs than their primary counterparts. In support of this, Osmak et al. 11 reported a study of drug-resistant cervical and ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Liang

O’Driscoll

McDonnell

et al. 2004

Intl Journal of Cancer

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“…The resistance observed was reversible after discontinuation of treatment, as demonstrated in our model. In spite of high levels of resistance in vivo, no significant resistance was observed when the cells from these tumours were exposed to the drugs in vitro, indicating that a very high level of resistance to anticancer drugs can develop through mechanisms that are exclusively in vivo (Teicher et al, 1990). Furthermore, Kobayashi et al (1993) have suggested that some forms of acquired drug resistance operate only at the multicellular level, as opposed to classic unicellular resistance mechanism.…”

Section: Discussionmentioning

confidence: 99%

No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan

et al. 2004

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CPT-11 (irinotecan) is a DNA-topoisomerase I inhibitor with preclinical activity against neuroblastoma (NB) xenografts. The aim was to establish in vivo an NB xenograft resistant to CPT-11 in order to study the resistance mechanisms acquired in a therapeutic setting. IGR-NB8 is an immature NB xenograft with MYCN amplification and 1p deletion, which is sensitive to CPT-11. Athymic mice bearing advanced-stage subcutaneous tumours were treated with CPT-11 (27 mg kg À1 day À1 Â 5) every 21 days (1 cycle) for a maximum of four cycles. After tumour regrowth, a new in vivo passage was performed and the CPT-11 treatment was repeated. After the third passage, a resistant xenograft was obtained (IGRNB8-R). The tumour growth delay (TGD) was reduced from 115 at passage 1 to 40 at passage 4 and no complete or partial regression was observed. After further exposure to the drug, up to 28 passages, the resistant xenograft was definitively established with a TGD from 17 at passage 28. Resistant tumours reverted to sensitive tumours after 15 passages without treatment. IGR-NB8-R remained sensitive to cyclophosphamide and cisplatin and cross-resistance was observed with the topoisomerase I inhibitor topotecan. No quantitative or qualitative topoisomerase I modifications were observed. The level of expression of multidrug resistance 1 (MDR1), MDR-associated protein 1 (MRP1) and, breast cancer resistance protein, three members of the ATP-binding cassette transporter family was not modified over passages. Our results suggest a novel resistance mechanism, probably not involving the mechanisms usually observed in vitro.

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“…To identify genes overexpressed in cyclophosphamideresistant EMT6/CTX mouse mammary tumor cells relative to sensitive parental EMT6 cells, 14 suppression-subtractive hybridization was performed using a PCR-Select kit (Clontech, Palo Alto, CA) and products were cloned and sequenced. BLAST analysis 15 (web address: http:// www.ncbi.nlm.nih.gov/BLAST) of one of the sequences revealed that it was identical to mouse SPF45 1 (GenBank AF083384).…”

Section: Cloning Of Spf45 Cdnamentioning

confidence: 99%

Human SPF45, a Splicing Factor, Has Limited Expression in Normal Tissues, Is Overexpressed in Many Tumors, and Can Confer a Multidrug-Resistant Phenotype to Cells

Sampath

Long

Shepard

et al. 2003

The American Journal of Pathology

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Our effort to identify novel drug-resistant genes in cyclophosphamide-resistant EMT6 mouse mammary tumors led us to the identification of SPF45. Simultaneously, other groups identified SPF45 as a component of the spliceosome that is involved in alternative splicing. We isolated the human homologue and examined the normal human tissue expression, tumor expression, and the phenotype caused by overexpression of human SPF45. Our analyses revealed that SPF45 is expressed in many, but not all, normal tissues tested with predominant expression in normal ductal epithelial cells of the breast, liver, pancreas, and prostate. Our analyses using tissue microarrays and sausages of tumors indicated that SPF45 is highly expressed in numerous carcinomas including bladder, breast, colon, lung, ovarian, pancreatic, and prostate. Interestingly, this study revealed that overexpression of SPF45 in HeLa, a cervical carcinoma cell line, resulted in drug resistance to doxorubicin and vincristine, two chemotherapeutic drugs commonly used in cancer. To our knowledge, this is the first study showing tumor overexpression of an alternate splicing factor resulting in drug resistance. The development of multidrug resistance is a major hurdle in the treatment of cancer. Although some genes that confer multidrug resistance are known, it is clear that many other genes remain to be identified. The characterization of novel mechanisms that lead to drug resistance would enable the development of a targeted new generation of anti-cancer drugs. To identify novel genes involved in drug resistance we performed suppressivesubtractive polymerase chain reaction analyses of the cyclophosphamide-resistant EMT6 mouse mammary tumor cells and the parental EMT6 tumors. This led to the identification of a gene that was highly homologous to a DNA damage response protein, DRT111 of Arabidopsis (unpublished observations). 1 While this work was in progress, Neubauer and colleagues, 1 identified a novel protein from the spliceosome. An analysis of all proteins present in the spliceosomal complex led to the identification of 25 previously identified proteins and 20 novel proteins. One of the novel proteins thus identified was named SPF45 (splicing factor 45 kd). This protein was identical to the one that was identified by our suppressive-subtractive polymerase chain reaction analysis. Neubauer and colleagues, 1 further showed that SPF45 was a nuclear protein that co-localizes with U1A snRNP in nuclear speckles, a known reservoir of splicing factors. [2][3][4] Recently Rappsilber and colleagues, 5 have described the identification of 311 proteins in the human spliceosomal complex of which 96 were novel proteins. Again, in this study, SPF45 was identified as a component of the spliceosome.Lallena and colleagues, 6 demonstrated that SPF45 regulates the alternate splicing of the Drosophila sexlethal gene (sxl). SXL protein is expressed only in female flies, but not in males. 7 Exon3 of Sxl plays a very important role in determining the expression of SXL because its inclus...

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Tumor Resistance to Alkylating Agents Conferred by Mechanisms Operative Only in Vivo

Cited by 285 publications

References 16 publications

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

Enhanced in vitro invasiveness and drug resistance with altered gene expression patterns in a human lung carcinoma cell line after pulse selection with anticancer drugs

No topoisomerase I alteration in a neuroblastoma model with in vivo acquired resistance to irinotecan

Human SPF45, a Splicing Factor, Has Limited Expression in Normal Tissues, Is Overexpressed in Many Tumors, and Can Confer a Multidrug-Resistant Phenotype to Cells

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