Phase II Study of Lonidamine in Cancer Patients

Band, Pierre R.; Deschamps, Michel; Besner, Jean‐Guy; Leclaire, Robert; Gervais, Pierre; Sanctis, Attilio De

doi:10.1159/000225889

Cited by 7 publications

(2 citation statements)

References 2 publications

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“…Its activity requires mi- Only a fraction of tumor cells have mitochondria in this state at any given time, and therefore, lonidamine-induced metabolic impairments alone are not likely to cause significant inhibition of tumor growth. In fact, lonidamine as a single agent has minimal tumoricidal activity [17][18][19]. Hyperthermia, radiation and some chemotherapeutic agents can induce cellular susceptibility to lonidamine, making them vulnerable to the drug's energy-depleting function.…”

Section: Discussionmentioning

confidence: 99%

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The combined use of radiation therapy and lonidamine in the treatment of brain metastases

DeAngelis¹,

Currie

Kim

et al. 1989

J Neuro-Oncol

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Lonidamine is an indazole carboxylic acid that has been shown to be synergistic with radiotherapy (RT) in tissue culture and animal models. Clinical experience has shown that lonidamine is well-tolerated, and appears to potentiate the activity of conventional chemotherapy in the treatment of brain metastases. A prospective randomized trial was undertaken to evaluate the use of lonidamine in combination with RT in the treatment of brain metastases. All patients received 3000 cGy of whole brain radiotherapy (WBRT). Fifty eight patients were enrolled; 31 received lonidamine plus WBRT and 27 received WBRT alone. There was no significant difference in response rate or survival between the treatment groups. Lonidamine blood levels were measured in 30 of the 31 patients who received the drug, and were therapeutic (greater than or equal to 15 micrograms/ml) in 50%. Survival and response rate were unaffected by the presence or absence of a therapeutic lonidamine level. The most common side-effects of lonidamine were myalgia, testicular pain, anorexia, and ototoxicity; however, only 2 patients had to discontinue the drug because of intolerable myalgias. No serious organ toxicity or myelosuppression was observed.

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Section: Discussionmentioning

confidence: 99%

“…The mean nadir white blood cell count (WBC) was 8.3 x 103/ram 3 (range: 0. [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22].0 x 103/ram3). Three patients had WBC below 2.0 x 103/mm3; 1 had tumor in his bone marrow and 2 others received systemic chemotherapy, 1 of whom also received pelvic RT.…”

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confidence: 99%

The combined use of radiation therapy and lonidamine in the treatment of brain metastases

DeAngelis¹,

Currie

Kim

et al. 1989

J Neuro-Oncol

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Effect of lonidamine on the cytotoxicity of four alkylating agents in vitro

Rosbe

Brann

Holden

et al. 1989

Cancer Chemother. Pharmacol.

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We examined the ability of lonidamine, which has been described as an inhibitor of cellular respiration and glycolysis, to enhance the cytotoxicity of alkylating agents to MCF-7 human breast-carcinoma cells. Lonidamine was increasingly cytotoxic to MCF-7 cells with increasing time of exposure. With a 12-h exposure, the IC50 for lonidamine was about 365 microM, and with a 24-h exposure it was about 170 microM. A drug concentration of 250 microM was chosen for use in the drug combination studies. Lonidamine appeared to have a dose-modifying effect on cisplatin (CDDP), producing increasingly supra-additive cell kill with increasing CDDP concentration. When simultaneously incubated with lonidamine for 1 h, 500 microM CDDP yielded a cell kill that was 2 log greater than additive cytotoxicity. Extending the exposure to lonidamine for 12 h after CDDP treatment led to a small, additional aliquot of cell kill of about 2.5-fold over the CDDP concentration range. Lonidamine also appeared to have a dose-modifying effect on melphalan cytotoxicity in the melphalan concentration range of 100-500 microM. Between concentrations of 10 and 100 microM melphalan, the drug combination survival after 1 h exposure fell within the envelope of additivity for the two agents. However, maintaining the presence of lonidamine for an additional 12 h increased the effect such that the combination was supra-additive over the entire concentration range of melphalan. Simultaneous exposure to 4-hydroperoxycyclophosphamide (4-HC) and lonidamine for 1 h resulted in greater than additive cell kill, and extending the lonidamine exposure period such that lonidamine was present during and 12 h after 4-HC treatment further increased this effect. Lonidamine had a moderate effect on the cytotoxicity of carmustine (BCNU) with a 1 h simultaneous exposure; however, this treatment combination reached greater than additive cytotoxicity only at the highest concentration of BCNU tested. Extending the lonidamine exposure time for an additional 12 h resulted in supra-additive cell kill over the BCNU concentration range. Therefore, when lonidamine was present during exposure to the alkylating agent and its presence was then extended for an additional 12 h, a synergistic cell kill was produced with all four alkylating agents tested.

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GLUT and HK: Two primary and essential key players in tumor glycolysis

Yadav,

Bhattacharya

et al. 2024

Seminars in Cancer Biology

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Phase II Study of Lonidamine in Cancer Patients

Cited by 7 publications

References 2 publications

The combined use of radiation therapy and lonidamine in the treatment of brain metastases

The combined use of radiation therapy and lonidamine in the treatment of brain metastases

Effect of lonidamine on the cytotoxicity of four alkylating agents in vitro

GLUT and HK: Two primary and essential key players in tumor glycolysis

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