In vitro cytotoxicity of novel platinum-based drugs and dichloroacetate against lung carcinoid cell lines.
BACKGROUND
Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines.


METHODS
Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay.


RESULTS
With exception of the highly chemoresistant UMC- 11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7-8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold.


CONCLUSIONS
The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.
Department of Internal Medicine I, Division of Oncology, St. Poelten Hospital, St. Poelten, Austria.
Wolfgang
W
Fiebiger
Ulrike
U
Olszewski
Ernst
E
Ulsperger
Klaus
K
Geissler
Gerhard
G
Hamilton
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D002276:Carcinoid Tumor / Q000188:drug therapy / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003603:Cytotoxins / Q000008:administration & dosage / Q000494:pharmacology; D003999:Dichloroacetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D017671:Platinum Compounds / Q000008:administration & dosage / Q000494:pharmacology*
D003603:Cytotoxins; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; C081294:satraplatin; D003999:Dichloroacetic Acid
Oncologist. 2005 Feb;10(2):123-31
15709214
Gastroenterology. 2005 May;128(6):1717-51
15887161
Cancer Chemother Biol Response Modif. 2005;22:471-83
16110625
J Thorac Oncol. 2010 Apr;5(4):453-9
20104194
Clin Cancer Res. 2008 Mar 15;14(6):1610-7
18347161
Ther Drug Monit. 1995 Feb;17(1):25-32
7725373
Anticancer Agents Med Chem. 2010 May;10(4):293-301
20187870
Cancer Chemother Pharmacol. 1998;42 Suppl:S31-43
9750027
Semin Oncol. 1997 Feb;24(1 Suppl 5):S5-12-S5-18
9122737
J Thorac Cardiovasc Surg. 1985 Jun;89(6):819-25
2582209
J Clin Oncol. 1983 Nov;1(11):727-40
6199469
Cancer Res. 1989 Aug 15;49(16):4640-7
2568175
Toxicology. 2008 Mar 12;245(1-2):35-48
18242812
Cancer. 1961 Sep-Oct;14:901-12
13771655
J Clin Oncol. 2005 Aug 1;23(22):4897-904
16051944
Clin Cancer Res. 1999 Oct;5(10):2742-7
10537337
Bull Cancer. 1997 Jun;84(6):603-8
9295863
J Clin Pharmacol. 1988 Aug;28(8):714-8
3216038
Cancer. 2001 Apr 15;91(8):1543-8
11301403
Eur J Surg Oncol. 1988 Dec;14(6):703-4
3192008
Best Pract Res Clin Endocrinol Metab. 2005 Jun;19(2):265-76
15763700
Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22199-204
20007777
Cancer Chemother Pharmacol. 1984;13(3):186-90
6386213
Trends Endocrinol Metab. 2009 Aug;20(6):287-94
19647447
J Clin Oncol. 1984 Nov;2(11):1255-9
6238136
Cancer. 1975 Aug;36(2):560-9
1157019
Ann Thorac Surg. 1995 Jan;59(1):78-83
7818364
Eur J Cardiothorac Surg. 2007 Feb;31(2):192-7
17196822
Future Oncol. 2009 Feb;5(1):33-42
19243296
Cancer. 1993 Jul 15;72(2):619-22
8391382
Ann Surg Oncol. 2009 Mar;16(3):649-55
19130141
Cancer Chemother Rep. 1975 May-Jun;59(3):547-56
128410
Breast Cancer Res Treat. 2010 Feb;120(1):253-60
19543830
Br J Cancer. 2008 Oct 7;99(7):989-94
18766181
Cancer Res. 1992 May 1;52(9 Suppl):2732s-2736s
1563005
Eur J Cardiothorac Surg. 1993;7(3):121-4; discussion 125
8384862
Endocr Relat Cancer. 2007 Jun;14(2):221-32
17639039
Cancer Chemother Pharmacol. 1990;27(2):157-60
2249333
Clin Cancer Res. 1998 Sep;4(9):2085-8
9748123
Cancer. 2009 Oct 1;115(19):4434-41
19562772
Virchows Arch. 1995;425(6):547-60
7697211
Ann Oncol. 1995 Feb;6(2):133-40
7786821
Clin Cancer Res. 2000 Apr;6(4):1205-18
10778943
Chest. 2000 Apr;117(4 Suppl 1):156S-162S
10777472
Ann Oncol. 1998 Sep;9(9):1003-8
9818075
Clin Pharmacol Ther. 1998 Dec;64(6):648-54
9871429
Oncologist. 2008 Dec;13(12):1255-69
19091780
J Clin Oncol. 2000 Mar;18(6):1331-6
10715305
World J Surg. 1996 Sep;20(7):908-14; discussion 914-5
8678970
N Engl J Med. 1986 Sep 11;315(11):663-6
2427948
Expert Rev Anticancer Ther. 2003 Dec;3(6):863-77
14686708
Neuroendocrinology. 2004;80(6):394-424
15838182
Am J Med Sci. 2010 Jan;339(1):68-76
19996730
J Clin Pharmacol. 1988 Mar;28(3):208-15
3283185