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Table 1 Drug sensitivity of breast-ovarian cancer syndrome related tumors: preclinical evidence

From: Drug therapy for hereditary cancers

Study Study design and main findings
BRCA1
Husain et al. [21] Antisense inhibition of BRCA1 expression in the cisplatin-resistant clone of SKOV3 ovarian cancer cell line restored sensitivity to the drug.
Bhattacharyya et al. [22] BRCA1-deficient mouse embryonic stem cells were more sensitive to cisplatin than isogenic BRCA1-proficient cells, as determined by a clonogenic assay.
Brodie et al. [45] Cell lines, which were generated from mammary tumors growing in genetically engineered BRCA1-deficient mice, demonstrated high sensitivity to doxorubicin in a cell survival assay.
Lafarge et al. [23] Inhibition of BRCA1 expression in HBL100 breast cancer cells led to increased sensitivity to cisplatin and etoposide, but resistance to paclitaxel and vincristine, as assessed by the rhodamine B proliferation test.
Moynahan et al. [42] Increased sensitivity of BRCA1-deficient mouse embryonic stem cells to mitomycin C in a clonogenic assay; reversed upon correction of BRCA1-mutated allele by gene targeting.
Mullan et al. [49] Tetracycline regulated inducible expression of BRCA1 in MBR62-bcl2 breast cancer cell line increased sensitivity to paclitaxel and vincristine, by did not affect the response to cisplatin, doxorubicin, cyclophosphamide, 5-fluorouracil, or bleomycin, as determined by a clonogenic assay.
Fedier et al. [24] Increased sensitivity of BRCA1-deficient mouse embryonic cells to the antiproliferative effect of camptothecin, topotecan, doxorubicin, mitoxantrone, etoposide, carboplatin, oxaliplatin, but not of 5-fluoroucil, gemcitabine, paclitaxel, docetaxel; increased apoptosis in response to doxorubicin but not to docetaxel.
Quinn et al. [25] BRCA1-deficiency is associated in increased sensitivity to apoptosis caused by etoposide, bleomycin or cisplatin, but resistance to apoptotic response to paclitaxel or vinorelbine.
Tassone et al. [26] BRCA1-mutant HCC1937 breast cancer cells were more sensitive to cisplatin, but less sensitive to doxorubicin and paclitaxel, than BRCA1-proficient MCF7 and MDA-MB-231 cells, as determined by the MTT test. Transfection of the wild-type BRCA1 in HCC1937 cells decreased their sensitivity to cisplatin, but restored sensitivity to doxorubicin and paclitaxel; this effect was at least in part attributed to the modulation of the apoptotic response.
Zhou et al. [52] SNU251 ovarian cancer cell line carrying truncation of 49 C-terminal aminoacids of the BRCA1 gene (partial deletion of 2nd BRCT domain) demonstrated increased sensitivity to paclitaxel in a cell viability assay; this effect was reversed by the introduction of the wild-type BRCA1.
Farmer et al. [57] siRNA directed or chemical inhibition of PARP profoundly inhibited clonogenicity of BRCA1-deficient mouse embryonic stem cells as compared to BRCA1-proficient isogenic cell lines; similar results were obtained upon simultaneous inhibition of BRCA1 and PARP in MCF7 breast cancer cell line. This effect was attributed to the massive growth arrest and subsequent apoptosis.
Tassone et al. [53] BRCA1-mutant HCC1937 breast cancer cells were more sensitive to vinorelbine than BRCA1-proficient MCF7 and MDA-MB-468 cells; when docetaxel was used, HCC1937 were similarly sensitive as compared to MCF7, and less sensitive than MDA-MB-468 (MTT test). Transfection of the wild-type BRCA1 in HCC1937 cells rendered resistance to vinorelbine, but slightly increased sensitivity to docetaxel. The effect of vinorelbine was at least in part attributed to the modulation of the apoptotic response.
Yun et al. [44] BRCA1-deficient mouse embryonic fibroblasts were significantly more sensitive to mitomycin C than BRCA1-wild-type expressing isogenic cells, as demonstrated by a clonogenic assay. The effect of mitomycin C is mediated through massive S-phase arrest followed by apoptosis.
Bartz et al. [29] BRCA1 inhibition strongly increased sensitivity of HeLa cells to cisplatin, as revealed by siRNA screen.
Chabalier et al. [50] siRNA-directed inactivation of BRCA1 function in MCF7 breast cancer cells rendered resistance to paclitaxel-induced growth inhibition and mitotic arrest.
Xing and Orsulic [30] BRCA1-deficient transformed mouse ovarian surface epithelial cell lines demonstrated higher sensitivity to cisplatin as compared to BRCA1-proficient isogenic cells, while no differential sensitivity to paclitaxel was observed.
Donawho et al. [31] Veliparib potentiated inhibitory effect of cisplatin, carboplatin and cyclophosphamide towards human BRCA1-mutated breast cancer xenografts (MX-1) growing in immunocompromised mice.
Rottenberg et al. [32] Doxorubicin, docetaxel and cisplatin inhibited growth of mammary tumors in genetically engineered BRCA1-deficient mice. Treated tumors eventually acquired resistance to doxorubicin and docetaxel, but not to cisplatin.
Treszezamsky et al. [48] BRCA1-mutant HCC1937 breast cancer cells showed increased sensitivity to etoposide as compared to BRCA1-wild-type expressing isogenic cells, as shown by a clonogenic assay.
Yamane et al. [117] BRCA1-mutant HCC1937 breast cancer cell line showed increased survival and decreased apoptosis in response 6-thioguanine as compared to BRCA1-wild-type expressing isogenic cells.
Shafee et al. [34] Cisplatin caused marked regression of BRCA1-deficient tumors growing in genetically engineered mice, while doxorubicin exerted only marginal effect.
Rottenberg et al. [59] Olaparib inhibited growth of mammary tumors in genetically engineered BRCA1-deficient mice. Combination of olaparib with cisplatin or carboplatin produced longer recurrence-free and overall survival than olaparib alone.
Promkan et al. [51] shRNA-directed inhibition of BRCA1 expression in MCF7 and MDA-MB-231 breast cancer cells decreased cytotoxicity of paclitaxel. Breast cancer cell lines carrying BRCA1 mutation (HCC1937 and MDA-MB-436) also demonstrated low sensitivity to paclitaxel.
Santarosa et al. [36] Antisense inhibition of BRCA1 expression in HBL100, MCF7 and T47D breast cancer cells led to increased sensitivity to mitomycin C and cisplatin, but not to doxorubicin and etoposide, as determined by a clonogenic assay. Similar results were obtained on the BRCA1-mutated HCC1937 breast cancer cell line. This effect was attributed to premature senescence of the chemosensitive cells.
Tassone et al. [37] Cisplatin induced almost complete growth inhibition of HCC1937-derived (BRCA1-mutated) breast cancer xenografts, while BRCA1-reconsituted HCC1937 xenografted tumors showed only partial response to cisplatin treatment.
Zander et al. [54] Topotecan inhibited growth of mammary tumors in genetically engineered BRCA1-deficient mice.
Drew et al. [39] AG014699 (PARP inhibitor) was highly cytotoxic against breast cancer cells with mutationally inactivated (MDA-MB-436) or epigenetically silenced (UACC3199) BRCA1, as determined by a clonogenic assay. BRCA1-deficient HCC1937 cells were more sensitive to AG014699 than the isogenic cell line with restored BRCA1 function (rhodamine B proliferation test). AG014699 and carboplatin efficiently inhibited growth of MDA-MB-436 and UACC3199 derived xenografted tumors.
Goldberg et al. [60] Nanoparticle-mediated delivery of PARP1-specific siRNA inhibited growth of BRCA1-deficient mouse ovarian cancer allografts; this effect was at least in part attributed to apoptotic death of targeted cells.
BRCA2
Abbott et al. [47] Increased sensitivity of BRCA2-deficient pancreatic cancer cell line CAPAN1 to mitoxantrone, etoposide and amsacrine, but not to paclitaxel, as assessed by a cell survival assay. Antisense down-regulation of BRCA2 in BRCA2-proficient pancreatic cancer cells resulted in hypersensitivity to mitoxantrone. CAPAN1 xenografted tumors showed nearly complete response to mitoxantrone and marked response to etoposide.
Yu et al. [41] Increased sensitivity of BRCA2-deficient vs. BRCA2-wild-type mouse lymphocytes to the mitomycin C, as determined by a cell survival assay.
Rahden-Staron et al, [55] Increased sensitivity of BRCA2-deficient Chinese hamster VS8 fibroblasts to camptothecin in a cell survival assay.
Samouelian et al. [27] Increased sensitivity of BRCA2-deficient ovarian cancer cell line TOV81 to cisplatin, but not to camptothecin or paclitaxel, as assessed by a cell survival assay.
van der Heijden et al. [28] Increased sensitivity of BRCA2-deficient pancreatic cancer cell line CAPAN1 to cisplatin and mitomycin C, as shown by a cell survival assay. Increased sensitivity to mitomycin C induced G2/M cell cycle growth arrest.
Bryant et al. [56] Chemical inhibition of PARP profoundly inhibited clonogenicity of BRCA2-deficient Chinese hamster VS8 fibroblasts as compared to parental V79 cells. Similar results were obtained upon simultaneous inhibition of BRCA2 and PARP in MCF7 and MDA-MB-231 breast cancer cell lines.
Farmer et al. [57] siRNA directed or chemical inhibition of PARP profoundly inhibited clonogenicity of BRCA2-deficient mouse embryonic stem cells as compared to BRCA2-proficient isogenic cell lines; similar results were obtained on BRCA2-deficient Chinese hamster ovarian cancer cell line. This effect was attributed to the massive growth arrest and subsequent apoptosis. Chemical PARP inhibitor suppressed growth of BRCA2-deficient xenografts in athymic mice.
Gallmeier and Kern [155], McCabe et al. [58] BRCA2-deficient CAPAN1 pancreatic cancer cells were sensitive to highly active PARP inhibitors, while moderately active PARP inhibitors did not affect cell survival.
van der Heijden et al. [43] BRCA2-deficient CAPAN1 xenografted tumors showed marked response to mitomycin C.
Bartz et al. [29] BRCA2 inhibition strongly increased sensitivity of HeLa cells to cisplatin, as revealed by siRNA screen.
Treszezamsky et al. [48] BRCA2-deficient EUFA423 fibroblasts showed increased sensitivity to etoposide as compared to BRCA1-wild-type expressing isogenic cells, as shown by a clonogenic assay.
Evers et al. [33] Olaparib, cisplatin, mitomycin C and temozolomide effectively inhibited growth of BRCA2-deficent vs. BRCA2-proficient mouse cell lines, while doxorubicin, docetaxel and 5-fluorouracil showed no difference. Synergism between olaparib and cisplatin was observed for BRCA2-deficient but not for BRCA2-proficient cells.
Hay et al. [35] BRCA2-deficient mammary tumors growing in genetically engineered mice demonstrated high sensitivity to olaparib and carboplatin.
Evers et al. [38] High-throughput pharmaceutical screen involving BRCA2-deficent vs. BRCA2-proficient mouse mammary tumor cell lines identified alkylating agents (chlorambucil, melphalane, nimustine) as the most potent and specific inhibitors of cell growth; differential inhibition was also registered for carboplatin, camptothecin and ellipticine. BRCA2-deficient mammary tumors, either transplanted or growing in genetically engineered mice, demonstrated high sensitivity to alkylating compounds. Synergistic interaction between alkylators and olaparib was observed both in vitro and in vivo.
Issaeva et al. [46] Chemical library screen identified 6-thioguanine as the most potent inhibitor of the survival of BRCA2-deficient human sarcoma U2OS cells and Chinese hamster VS8 fibroblasts. High efficacy of both 6-thioguanine and AG014699 (PARP inhibitor) against BRCA2-deficient xenografted tumors. Comparison of BRCA2-deficient VS8 cells versus isogenic BRCA2-expressing VS8+B2 cells: higher sensitivity to temozolomide, camptothecin and doxorubicin, but lower sensitivity to gemcitabine and paclitaxel.
Drew et al. [39] AG014699 (PARP inhibitor) was highly cytotoxic against BRCA2-deficient CAPAN1 pancreatic cancer cells, as determined by a clonogenic assay. AG014699 and carboplatin efficiently inhibited growth of CAPAN1-derived tumor xenografts, with the most pronounced effect while using combination of these drugs.
Kortmann et al. [40] BRCA2-deficient ovarian cancer xenografts showed marked response to olaparib, carboplatin, and olaparib plus carboplatin, whereas BRCA2-proficient xenografts responded only to carboplatin and olaparib plus carboplatin.
PALB2
Villarroel et al. [97] High sensitivity of PALB2-deficient xenografted pancreatic tumor to mitomycin C and cisplatin but not to gemcitabine.
Other genes
McCabe et al. [93] RNA-interference driven inhibition of NBN (NBS1), CHEK2 or some other genes involved in homologous recombination increased sensitivity of cultured cells to PARP inhibitors, as determined by cell survival assays.
Bartz et al. [29] BRIP1 inhibition strongly increased sensitivity of HeLa cells to cisplatin, as revealed by siRNA screen.