Potentiation of cisplatin and carboplatin cytotoxicity by amphotericin B in different human ovarian carcinoma and malignant peritoneal mesothelioma cells

Our plain-English summary of Potentiation of cisplatin and carboplatin cytotoxicity by amphotericin B in different human ovarian carcinoma and malignant peritoneal mesothelioma cells, by L. Poulain, F. Sichel, H. Crouet, et al (Cancer Chemotherapy and Pharmacology, 1997).

The study

• Authors: L. Poulain, F. Sichel, H. Crouet, F. Bureau, P. Gauduchon, M. Gignoux, J.Y. Le Talaër
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 1997;40(5):385-90
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

An in vitro study of the combined cytotoxicity of either cisplatin (CDDP) or carboplatin and amphotericin B (AmB) was undertaken on a set of different ovarian carcinoma (IGROVI, IGROVI-C10, OAW42) and peritoneal malignant mesothelioma (CFB-CARP1) cell lines and ascitic cells freshly obtained from ovarian cancer patients so as to investigate the possibility of overcoming their resistance to platinum compounds. Growth-inhibition curves obtained 6 days after a 2-h period of exposure to the drugs showed that AmB at 5-10 mg/l allowed a 5- to 10-fold decrease in the 50% growth-inhibitory concentrations (IC50) of CDDP and carboplatin on either sensitive or resistant cells. Intracellular platinum assays with IGROVI cells showed that AmB acted by increasing dramatically the platinum uptake at a proportion that accounted for the increase in cytotoxicity. In the subline IGROVI-C10, a 10-fold resistant subline of IGROVI, AmB at 10 mg/l allowed recovery to the level of sensitivity seen in the parental cell line in the absence of AmB but not to the level observed in the presence of AmB. Acquisition of resistance mechanisms that are independent of the regulation of platinum uptake might be involved in this cell line. Thus, AmB might act by increasing the intracellular concentration of platinum without modifying the resistance mechanism involved downstream. However, in our models an increase in the intracellular level of platinum was always sufficient for the recovery of chemosensitivity in vitro. We also show that the phosphodiesterase inhibiting methylxanthines act synergistically with AmB. The latter drugs are weakly toxic and could also attenuate the nephrotoxicity of AmB.

In plain English

This was a laboratory study of human cancer cells grown in dishes. It did not study people or asbestos exposure, and the article does not discuss asbestos. The authors tested whether amphotericin B, an antifungal drug, made two platinum chemotherapy drugs, cisplatin and carboplatin, more toxic to cancer cells. They used ovarian carcinoma cell lines (IGROV1, OAW42, and IGROV1-C10, a cisplatin-resistant subline of IGROV1), one malignant peritoneal mesothelioma cell line (CFB-CARP1), and cells grown from the abdominal fluid of three ovarian cancer patients. The cells were exposed to the drugs for 2 hours. In IGROV1 cells, amphotericin B at 5 mg/l cut five-fold the cisplatin concentration needed to halve cell growth. It also raised platinum inside the cells 3.6-fold. In the resistant subline, amphotericin B at 10 mg/l restored the sensitivity the parent cells had without amphotericin B. Two methylxanthine drugs, pentoxifylline and theophyllin, acted synergistically with amphotericin B. The authors concluded that amphotericin B combined with carboplatin was very efficient against tumor cells taken from patients, including resistant cells.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: In vitro laboratory study of drug cytotoxicity in cultured human cancer cells
• Who was studied: The cells studied were: ovarian adenocarcinoma cell lines IGROV1 and OAW42; IGROV1-C10, a cisplatin-resistant subline of IGROV1 made in the laboratory; CFB-CARP1, a malignant peritoneal mesothelioma cell line of the epithelial type grown from the ascitic fluid of a patient at the Centre François Baclesse in Caen, France; and ascitic cell cultures AU1, CR1 and FOR1 from three ovarian cancer patients.
• Exposure: No asbestos exposure was studied. Cells were exposed for 2 hours to cisplatin or carboplatin, alone or together with amphotericin B (mainly 5 or 10 mg/l). Some experiments also used the methylxanthines pentoxifylline and theophyllin.
• Main results:
  • In IGROV1 ovarian cancer cells, amphotericin B at 5 mg/l reduced the 50% growth-inhibitory concentration (IC50) of cisplatin five-fold (P < 0.01). Without amphotericin B, the cisplatin IC50 was around 5 mg/l.
  • Amphotericin B alone was toxic to IGROV1 cells only at doses above 10 mg/l. Its own IC50 was around 40 mg/l.
  • In IGROV1 cells, 2 hours of carboplatin alone did not reach an IC50 even at 500 mg/l. With amphotericin B at 10 mg/l, the carboplatin IC50 was about 100 mg/l. A 24-hour exposure to carboplatin alone gave an IC50 of around 25 mg/l.
  • In IGROV1 cells, amphotericin B at 5 mg/l increased the platinum level inside the cells 3.6-fold and decreased the cisplatin IC50 five-fold.
  • The IGROV1-C10 subline was 10-fold more resistant to cisplatin than the parent IGROV1 cells. Amphotericin B at 10 mg/l brought its sensitivity back to the parent cells' IC50 without amphotericin B (P < 0.005), but not to the parent cells' level with amphotericin B.
  • In IGROV1-C10 cells, pentoxifylline and theophyllin acted synergistically with amphotericin B to increase cisplatin's toxicity. Similar results were seen in a CFB-CARP1 mesothelioma subline that had become 2 times more resistant to cisplatin.
  • Across the ovarian carcinoma lines, the CFB-CARP1 mesothelioma line and the ovarian ascitic cells, amphotericin B at 10 mg/l lowered the IC50 of cisplatin and carboplatin by a factor of 5 to 10. The exception was OAW42 cells, which were already very sensitive to carboplatin without amphotericin B.
• The authors' conclusion: The authors concluded that amphotericin B combined with carboplatin was very efficient against ex vivo cultures of tumor cells from patients, including resistant ones, and against a spontaneously resistant malignant mesothelioma cell line.
• Limitations the authors state:
  • For the CR1 patient cell culture, the authors noted that mesothelial cells contaminating the culture during the toxicity test could have altered how the result was interpreted.
  • The authors stated that the combination of cisplatin and amphotericin B appears too toxic to the kidneys for clinical use.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Ovarian cancer, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Cisplatin, Carboplatin, Carcinoma, Peritoneal Mesothelioma, Mesothelioma, Ovarian Cancer, Nephrotoxicity.

Related studies

• Administration of cisplatin in three patients with carboplatin hypersensitivity: is skin testing useful? — E. Syrigou, N. Makrilia, et al. (2010)
• Randomised phase II study of cisplatin-etoposide versus infusional carboplatin in advanced non-small-cell lung cancer and mesothelioma — S.C. White, H. Anderson, et al. (2000)
• Platinum-DNA damage in leukocyte DNA of patients receiving carboplatin and cisplatin chemotherapy, measured by atomic absorption spectrometry — R.J. Parker, I. Gill, et al. (1991)
• Anticancer effect of bromelain with and without cisplatin or 5-FU on malignant peritoneal mesothelioma cells — K. Pillai, A. Ehteda, et al. (2014)
• The tocotrienol-rich fraction from rice bran enhances cisplatin-induced cytotoxicity in human mesothelioma H28 cells — K. Nakashima, N. Virgona, et al. (2010)
• Flow cytometric measurement of cellular FLICE-inhibitory protein (c-FLIP) in ovarian carcinoma effusions — H.P. Dong, A.K. Ree Rosnes, et al. (2011)

Browse more research in Cancer Chemotherapy and Pharmacology, or return to medical research.