Phase I study of mitomycin C and menadione in advanced solid tumors

  title={Phase I study of mitomycin C and menadione in advanced solid tumors},
  author={Kim A Margolin and Steven A. Akman and Lucille A. Leong and Robert J. Jr. Morgan and George Somlo and James W. Raschko and Chul Ahn and James H. Doroshow},
  journal={Cancer Chemotherapy and Pharmacology},
A phase I study of mitomycin C with menadione (2-methyl-1,4-naphthoquinone, a vitamin K analogue which lowers intracellular pools of reduced glutathione) was designed as an approach to overcoming tumor cell resistance to alkylating agent chemotherapy. Patients with refractory solid tumors (n=51) were treated with a 48-h continuous intravenous infusion of menadione followed by a bolus intravenous dose of mitomycin C at the completion of the menadione infusion. Initial menadione doses of 8.0 and… 

Phase I trial of menadiol diphosphate (vitamin K3) in advanced malignancy

A phase I trial of M in patients with advanced cancer with median patient age, Karnofsky performance status, and number of prior chemotherapy regimens, finding no objective partial or complete responses was observed.

Menadione serves as a substrate for P-glycoprotein: implication in chemosensitizing activity

Menadione may be a promising chemotherapeutic enhancer by its ability of circumventing drug resistance, in addition to its own anti-cancer activity.

The In Vitro and In Vivo Antitumor Activity of Vitamin C: K3 Combinations Against Prostate Cancer

Experimental animal studies indicate that autoschizis is also evident when the vitamin combination is administered to nude mice with implanted human prostate tumors, suggesting that the Vitamin C and vitamin K3 combination may offer great potential as a new antitumoral chemotherapy.

Apoptosis Induction by Menadione in Human Promyelocytic Leukemia HL-60 Cells

The results showed that menadi-one induced mixed types of cell death, apoptosis at low concentrations and necrosis at high concentrations in HL-60 cells.

Synergy Effect of Vitamin K3 on Cytotoxicity of Campthotecin in HCT116 Cells

Findings raised the possibility that the chemotherapy of vitamin K3 (MK0) with topoisomerase I poison may be useful for the improvement of patients with malignancy in clinic.

Vitamin C and K3 Combination Causes Enhanced Anticancer Activity against RT-4 Bladder Cancer Cells

VC:VK3 was able to cause autoschizic cell death through oxidative stress, thiol depletion, lipid peroxidation, modification of ATP levels and calcium regulation, and was granted orphan drug status for the treatment of metastatic or locally advanced, inoperable transitional cell carcinoma of the urothelium.

Schisandrin B protects against menadione-induced hepatotoxicity by enhancing DT-diaphorase activity

The ensemble of results suggests that the ability of Sch B pretreatment to enhance hepatocellular DTD activity may at least in part be attributed to the protection against menadione hepatotoxicity.

Novel therapy for locally advanced triple-negative breast cancer

ERK plays a critical role in VK3-induced growth inhibition, and it will be the focus of next steps in the development of molecular therapy for TNBC.

Differential behaviors of trastuzumab-sensitive and -resistant SKBR3 cells treated with menadione reveal the involvement of Notch1/Akt/FOXO1 signaling elements

Based on the extent of apoptosis, colony formation and wound healing assays, M alone, and/or in combination with T had a stronger inhibitory effect on proliferation of SKBR3R cells relative toSKBR3S cells, which would be of value in designing more efficient chemosensitization strategies.



Phase I clinical trial of intravenous L-buthionine sulfoximine and melphalan: an attempt at modulation of glutathione.

  • H. BaileyR. Mulcahy D. Spriggs
  • Medicine
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 1994
This study shows that BSO alone and in combination with L-PAM can be safely given to patients, but that a schedule of short infusions every 12 hours does not result in GSH depletion less than 30% of baseline values.

New findings in the pharmacokinetic, metabolic, and drug-resistance aspects of mitomycin C.

  • R. Dorr
  • Biology, Chemistry
    Seminars in oncology
  • 1988
There was no evidence of dose dependent pharmacokinetics over a wide range of doses and patient populations, including pediatric solid tumor patients, and new observations of the development of the multidrug-resistance phenotype in mitomycin C-treated L-1210 cells in vitro.

Selective enhancement by menadiol of in vitro drug activity in human lymphatic neoplasms.

Cell survival times with mechlorethamine, vincristine, and dexamethasone were converted from a range characteristic of drug resistance to a range of drug sensitivity in the presence of menadiol, which is probably clinically achievable.

Synergistic cytotoxicity between menadione and dicumarol vs. murine leukemia L1210.

Isobolographic analysis of the effect of K3-dicumarol combinations, in the concentration ranges between 5 and 75 microM, on L1210 growth, indicated synergy between the two drugs, and it was possible that effects on the glutathione and/or NADPH pools contributed.

Vitamin K in the treatment of cancer.

Cancer-associated hemolytic-uremic syndrome: analysis of 85 cases from a national registry.

Recommendations include careful monitoring of renal and hematologic function in patients treated with MMC, aggressive nontransfusion in patients with suspected C-HUS, and consideration of treatment with SPA immunopheresis in Patients with definite syndrome.

Effect of buthionine sulfoximine and ethacrynic acid on cytotoxic activity of mitomycin C analogues BMY 25282 and BMY 25067.

A potentiation of the cytotoxic activity of MMC or BMY 25282 can be achieved by GSH depletion and/or GST inhibition, and the enhanced cytotoxicity of BMY 25067 may be caused at least in part by the increased formation of drug-DNA cross-links, which has been suggested to play an important role in cellular resistance to several cancer chemotherapy drugs.

Vitamin K3 inhibition of malignant murine cell growth and human tumor colony formation.

To assess the antineoplastic potential of vitamin K compounds, the effects of vitamin K3 (menadione), vitamin K1 (phylloquinone), and warfarin on L1210 murine leukemia cell growth were studied in a

Effect of artificial electron acceptors on the cytotoxicity of mitomycin C and doxorubicin in human lung tumor cells.