Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy with or without Cisplatinum for Head and Neck Cancer

Hamstra, Daniel A.; Eisbruch, Avraham; Naidu, M. U. R.; Ramana, Gogula V.; Sunkara, Prasad S.; Campbell, Kathleen C.M.; Ross, Brian D.; Rehemtulla, Alnawaz

doi:10.1158/1078-0432.ccr-09-3318

Cited by 25 publications

(17 citation statements)

References 40 publications

(75 reference statements)

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“…Several animal studies have shown that D-Met prevented oxidative-stress induced ototoxicity and nephrotoxicity from cisplatin treatment (Campbell et al, 1996;Reser et al, 1999). Hamstra et al (2010) evaluated the safety of the MRX-1024 -the bioavailable suspension of D-Met -in cancer patients. They showed that MRX-1024 decreased the rate and severity of oral mucositis, with no significant increase in toxicity.…”

Section: Introductionmentioning

confidence: 99%

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

Gopal

Shrestha

et al. 2012

Neurotoxicology and Teratology

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Cisplatin is a platinum-based chemotherapeutic agent widely used for the treatment of various types of cancer. Patients undergoing cisplatin treatment often suffer from a condition known as "chemobrain", ototoxicity, peripheral neuropathy, weight loss, nausea, vomiting, nephrotoxicity, seizures, hearing loss and tinnitus.D-Methionine (D-Met), a sulfur-containing nucleophilic antioxidant, has been shown to prevent cisplatininduced side effects in animals without antitumor interference. In this study, we have used an in vitro model of cortical networks (CNs), enriched in auditory cortex cells; to quantify cisplatin neurotoxicity and the protective effects of D-Met. Dissociated neurons from auditory cortices of mouse embryos were grown on microelectrode arrays with 64 transparent indium-tin oxide electrodes, which enabled continuous optical and electrophysiological monitoring of network neurons. Cisplatin at 0.10-0.25 mM induced up to a 200% increase in spontaneous spiking activity, while concentrations at or above 0.5 mM caused irreversible loss of neuronal activity, accompanied by cell death. Pretreatment with D-Met, at a concentration of 1.0 mM, prevented the cisplatin-induced excitation at 0.10-0.25 mM, caused sustained excitation without occurrence of cell death at 0.5 mM, and delayed cell death at 0.75 mM cisplatin. L-Methionine, the optical isomer, showed lower potency and less efficacy than D-Met, was less protective against 0.1 mM cisplatin, and proved ineffective at a concentration of 0.5 mM cisplatin. Pre-exposure time of D-Met was associated with the protective effects at 0.1 and 0.5 mM cisplatin, with longer pre-exposure times exhibiting better protection. This study quantifies as a function of concentration and time that D-Met protects central nervous system tissue from acute cisplatin toxicity.

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Section: Introductionmentioning

confidence: 99%

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

Gopal

Shrestha

et al. 2012

Neurotoxicology and Teratology

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“…The long clinical use of D‐met plus the preclinical data showing protection from mucosal injury led to a previously reported phase I clinical trial in which 25 patients with SCCHN were treated with fractioned RT (with 78% also receiving cisplatin) . Pharmacokinetic analysis revealed that when administered orally at 100 mg/kg, peak and area under the curve (AUC) levels of D‐met were comparable to the levels previously associated with mucosal protection in rodents.…”

Section: Introductionmentioning

confidence: 81%

Double‐blind placebo‐controlled multicenter phase II trial to evaluate D‐methionine in preventing/reducing oral mucositis induced by radiation and chemotherapy for head and neck cancer

et al. 2018

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“…D-met reportedly provides selective protection for non-transformed, versus transformed, cells (7), in keeping with our observation that it does not affect tumor growth ± radiation. The use of D-met in human studies resulted in mild-moderate side effects, but it appeared beneficial for limiting the occurrence of severe oral mucositis (8). Racemic mixtures of D- and L-met have long been used for acetaminophen-induced hepatotoxicity (e.g., 21).…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Protection From Radiation ± Cisplatin-Induced Oral Mucositis

Cotrim

Yoshikawa

Sunshine

et al. 2012

International Journal of Radiation Oncology*Biology*Physics

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Purpose To evaluate if two pharmacological agents, Tempol and D-methionine (D-met), are able to prevent oral mucositis in mice following exposure to ionizing radiation ± Cisplatin. Methods and Materials Female C3H mice, ~8 weeks old, were irradiated with five fractionated doses ± Cisplatin to induce oral mucositis (lingual ulcers). Just prior to irradiation and chemotherapy, mice were treated, either alone or in combination, with different doses of Tempol (by intraperitoneal, ip, injection or topically, as an oral gel) and D-met (by gavage). Thereafter, mice were sacrificed, tongues harvested and stained with a solution of Toluidine Blue. Ulcer size and tongue epithelial thickness were measured. Results Significant lingual ulcers resulted from 5 × 8 Gy radiation fractions, which were enhanced with Cisplatin treatment. D-met provided stereospecific partial protection from lingual ulceration after radiation. Tempol, via both routes of administration, provided nearly complete protection from lingual ulceration. D-met plus a suboptimal ip dose of Tempol also provided complete protection. Conclusions Two fairly simple pharmacological treatments were able to markedly reduce chemoradiation-induced oral mucositis in mice. This proof of concept study suggests that Tempol, alone or in combination with D-met, may be a useful and convenient way to prevent the severe oral mucositis that results from head and neck cancer therapy.

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Pharmacokinetic Analysis and Phase 1 Study of MRX-1024 in Patients Treated with Radiation Therapy with or without Cisplatinum for Head and Neck Cancer

Cited by 25 publications

References 40 publications

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

d-Methionine protects against cisplatin-induced neurotoxicity in cortical networks

Double‐blind placebo‐controlled multicenter phase II trial to evaluate D‐methionine in preventing/reducing oral mucositis induced by radiation and chemotherapy for head and neck cancer

Pharmacological Protection From Radiation ± Cisplatin-Induced Oral Mucositis

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