Motexafin Gadolinium (MGd): Targeting Oxidative Stress Pathways for the Treatment of Non-Hodgkin's Lymphoma

Reviewer: Christopher Dolinsky, MD
University of Pennsylvania School of Medicine
Ultima Vez Modificado: 7 de noviembre del 2005

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Presenter: Andrew M. Evans, DO, MSCI
Presenter's Affiliation: Northwestern University, Chicago, Illinois
Type of Session: Scientific

Background

  • Motexafin Gadolinium (MGd or Xcytrin) is a novel anti-cancer agent which disrupts redox- dependent pathways by targeting oxidative stress-related proteins.
  • This agent has been shown to work synergistically with radiation, rituximab, and various chemotherapy agents.
  • By disrupting enzymes like thioredoxin and metallothionenes in tumor cells, MGd prevents tumors from handling significant oxidative stresses.
  • MGd tends to accumulate in tumor cells, and is detectable by MRI.
  • MGd has been studied in >800 patients and found to be well tolerated.
  • MGd's activity works though a mechanism known as "futile redox cycling", whereby MGd transfers electrons to molecular oxygen to create reactive oxygen species and cause oxidative stress in tumor cells.
  • MGd was originally studied in conjunction with radiation therapy.
  • There have been several preclinical trials which show an enhancement of radiation-induced cell killing when adding MGd.
  • MGd can cause cytotoxicity in multiple myeloma cell lines which are resistant to chemotherapy and dexamethasone.
  • MGd has been studied in lymphoma cell lines, and demonstrated to induce apoptosis.
  • Based on preclinical work, MGd appears more effective in B-cell lines than T-cell lines.
  • Laboratory work has also shown MGd to work synergistically with rituximab.
  • Lymphoma cells tend to have highly elevated intracellular uptake of MGd.
  • Because MGd contains the ferromagnetic compound gadolinium and it tends to accumulate in malignant cells, it can be used as a contrast agent during MRI scans.

Materials and Methods

  • Radioimmunotherapy remains a safe and effective treatment therapy for Non-Hodgkins' Lymphoma (NHL).
  • Radioimmunotherapy employs radiolabelled antibodies against the B-cell marker CD20.
  • One such compound is Yttrium 90 Irbitumomab Tiuxetan (Zevalin), and it has activity in rituximab- refractory NHL patients, as demonstrated by multiple clinical trials.
  • Zevalin with MGd may be synergistic and could provide high, durable response rates.
  • The Northwestern group has been enrolling patients on a modified Phase I/II trial of combination Zevalin and MGd for patients with relapsed or refractory low-grade or follicular NHL.
  • A static dose of Zevalin is employed, with a dose escalation of MGd utilized.
  • Nine of 10 treated patients are evaluable (4 female, 5 male), with 2 dose levels of MGd (2.5 mg/mg and 3.5 mg/kg).
  • The median age of the patients is 57 (range 37-80).
  • Histologies include 6 follicular, 2 transformed diffuse large B-cell, and 1 mantle-cell lymphoma.
  • The median number of prior therapies is 3 (range 1-4).
  • 7/9 patients were refractory to rituximab (defined as no response or time to treatment progression < 6 months).

Results

  • Currently no dose limiting toxicities have been seen (defined as either grade 3 or 4 non-hematologic or grade 4 hematologic toxicities).
  • Either a complete response (CR) or partial response (PR) to therapy was seen in 7/9 patients.
  • A 100% response rate was seen in the subset of follicular lymphoma patients (86% complete response rate).
  • Of 7 responders, response (by CT scan) was documented at 4 weeks in all patients.
  • Tolerability has been very similar to single agent Zevalin.
  • One patient relapsed at 8 months (dose level 1), and the other 6 patients remain in remission at 15, 14, 9, 9, 5 and 3 months from therapy.

Author's Conclusions

  • Significant cytotoxic activity with MGd alone has been seen in resistant myeloma and lymphoma cells.
  • This appears to be mediated through apoptosis and targeting oxidative stress proteins.
  • MGd, at doses of 2.5 and 3.5 mg/mg x 8 given with Zevalin, is safe, and does not appear to increase hematologic or other toxicity.
  • Prompt tumor responses and a high proportion of CRs in rituximab-refractory follicular patients were seen with the combination of MGd and Zevalin.
  • MGd should be pursued in hematologic malignancy clinical trials as single-agent and/or combination therapy with chemotherapy and/or radiation.

Clinical/Scientific Implications

Dr. Evans presented exciting research using MGd, a novel compound which can target the oxidative stress pathways of tumor cells. The fact that all 7 of the relapsed or refractory follicular lymphoma patients had at least a partial response to Zevalin/MGd is quite remarkable. This is certainly a promising new drug, and it is only a matter of time before this compound is tested in a variety of other settings. With more mature follow-up, we may have a better idea of the duration of response to the Zevalin/MGd combination. Radioimmunotherapy is being tested as first line therapy for NHL, and it is only a matter of time before radioimmunotherapy with MGd will be tested in that same setting. Radiation therapy is thought to kill cells via oxidative stress, and it would be very interesting to test MGd with ionizing radiation in a clinical trial. Dr. Evans and his colleagues should be commended for this well designed and fascinating research.



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