Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts

Our plain-English summary of Leucovorin rescue allows effective high-dose pralatrexate treatment and an increase in therapeutic index in mesothelioma xenografts, by P.M. Tedeschi, Y.K. Kathari, I.N. Farooqi, et al (Cancer Chemotherapy and Pharmacology, 2014).

The study

• Authors: P.M. Tedeschi, Y.K. Kathari, I.N. Farooqi, J.R. Bertino
• Journal: Cancer Chemotherapy and Pharmacology
• Published: 2014;74(5):1029-32
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.

Methods: H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.

Results: In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.

Conclusions: High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.

In plain English

This laboratory study tested a cancer drug, pralatrexate, on mesothelioma cells and on mice carrying mesothelioma tumors. It did not study asbestos exposure. First, the authors treated a pleural mesothelioma cell line called H2052 with three antifolate drugs: methotrexate, pralatrexate and pemetrexed. In some tests they added leucovorin, a form of folate, 24 hours later. The cells were more sensitive to pralatrexate than to methotrexate (IC50 values of 0.625 nM versus 80 nM) and more sensitive to it than to pemetrexed. Leucovorin slightly raised the IC50 for methotrexate and pemetrexed, and its effect on pralatrexate was seen only at high concentrations. Next, female nude mice carrying H2052 tumors received pralatrexate at 60 or 180 mg/kg, with or without leucovorin. At 60 mg/kg, tumors shrank either way, but mice given leucovorin had less toxicity. At 180 mg/kg without leucovorin, mice lost a large amount of weight and had to be killed. With leucovorin they lost some weight and had a durable response lasting several weeks. The authors concluded that this approach may be a viable treatment strategy in mesothelioma.

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: Laboratory study: in vitro cell experiments followed by an animal (mouse xenograft) experiment
• Who was studied: The H2052 pleural mesothelioma cell line, and 8- to 10-week-old female nude mice injected under the skin with 5 million H2052 cells (Rutgers Cancer Institute of New Jersey). The number of mice per group is not stated.
• Exposure: No asbestos exposure was studied. The exposures were drugs. In cells: methotrexate, pralatrexate or pemetrexed for 24 h, with or without 2 μM leucovorin afterwards. In mice: saline control; pralatrexate 60 or 180 mg/kg on days 1, 4 and 7, with or without leucovorin 50 mg/kg at 24, 32 and 48 h after each dose; or leucovorin alone.
• Main results:
  • In H2052 cells, the IC50 was 0.625 nM for pralatrexate and 80 nM for methotrexate
  • H2052 cells were also more sensitive to pralatrexate than to pemetrexed
  • In cells, adding 2 μM leucovorin raised the IC50 slightly for methotrexate and pemetrexed. Its effect on pralatrexate was seen only at high pralatrexate concentrations.
  • In mice given 60 mg/kg pralatrexate, tumors regressed with and without leucovorin and efficacy was nearly identical. Mice given leucovorin had less toxicity, and their bodyweight stayed close to control animals.
  • In mice given 180 mg/kg pralatrexate without leucovorin, the mice lost a large amount of weight, had poor body condition scores and had to be killed under institutional protocol
  • In mice given 180 mg/kg pralatrexate with leucovorin rescue, there was some weight loss and a durable tumor response lasting several weeks
• The authors' conclusion: The authors concluded that high-dose pralatrexate followed by leucovorin rescue may be a viable treatment strategy in mesothelioma and other cancers, and that adding leucovorin rescue to pralatrexate protocols should be explored in the clinic.
• Limitations the authors state:
  • The authors note that the dose schedule would need to be optimized in patients

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Antifolate, Pemetrexed (Alimta).

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