High-performance liquid chromatographic determination and stability of 5-(3-methyltriazen-1-yl)-imidazo-4-carboximide, the biologically active product of the antitumor agent temozolomide, in human plasma

Kim, Hong Ki; Lin, Chinsu; Parker, Donald; Veals, J.; Lim, Josephine; Likhari, Paul; Statkevich, Paul; Marco, Aliceann; Nomeir, Amin A.

doi:10.1016/s0378-4347(97)00431-3

Cited by 39 publications

(26 citation statements)

References 10 publications

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“…8 Bioavailability of temozolomide following oral administration in dogs is 100%, and there is no clinically important metabolism or accumulation of the drug in the body. 12 The main route of temozolomide excretion in dogs is through the kidneys, with minimal excretion taking place through the feces or respiratory tract. Dogs appear to be more sensitive to temozolomide than humans, in that the maximum nonlethal dose for dogs (200 mg/m 2 ) is similar to the therapeutic dose for humans.…”

Section: Discussionmentioning

confidence: 99%

Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma

Dervisis¹,

Domı́nguez²,

Sarbu³

et al. 2007

javma

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ObjectiveTo compare results of treatment with temozolomide or dacarbazine, in combination with an anthracycline, in dogs with relapsed or refractory lymphoma. DesignNonrandomized, controlled clinical trial. Animals63 dogs with relapsed or refractory lymphoma. ProceduresChemotherapy was administered in 21-day cycles. A combination of temozolomide and an anthracycline (doxorubicin or dactinomycin) was administered to 21 dogs and a combination of dacarbazine and an anthracycline was administered to 42 dogs. Efficacy and toxicoses were assessed. ResultsThirteen of the 18 (72%) dogs treated with the temozolomide-anthracycline combination and 25 of the 35 (71%) dogs treated with the dacarbazine-anthracycline combination had a complete or partial response. Median duration of response to rescue chemotherapy was 40 days (range, 0 to 217 days) for dogs in the temozolomide group and 50 days (range, 0 to 587 days) for dogs in the dacarbazine group. The incidence of high-grade hematologic toxicoses was significantly higher among dogs in the dacarbazine group than among dogs in the temozolomide group, but the incidence of gastrointestinal tract toxicoses was not significantly different between groups. There were no significant differences between groups in regard to proportion of dogs with a complete or partial response, duration of response to rescue chemotherapy, survival time following rescue chemotherapy, or overall survival time.Conclusions and Clinical RelevanceBoth combinations had promise in the treatment of dogs with relapsed or refractory lymphoma, although administration of temozolomide was more convenient than administration of dacarbazine and caused fewer hematologic toxicoses. (J Am Vet Med Assoc 2007;231:563-569)

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Section: Discussionmentioning

confidence: 99%

Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma

Dervisis¹,

Domı́nguez²,

Sarbu³

et al. 2007

javma

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“…To simulate clinical isolated limb infusion, the drug concentration is f10 times the published plasma level of temozolomide in patients treated with a systemic therapy. Temozolomide was not removed after application as the halflife of temozolomide and its active metabolite, 5-(3-methyltriazen-1-yl)imidazole-4-carboximide, is f2 hours (19). After 48 hours, cells were trypsinized and collected together with the cells floating in the medium.…”

Section: Methodsmentioning

confidence: 99%

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

Ko¹,

Ueno²,

Yoshimoto³

et al. 2006

Clinical Cancer Research

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Purpose: Previous preclinical studies have shown that regional temozolomide therapy via isolated limb infusion is more effective than melphalan, the current drug of choice for regional chemotherapy for advanced extremity melanoma. The aim of this study was to determine whether hyperthermia could further augment the efficacy of temozolomide, an alkylating agent, against melanoma and improve its therapeutic index in a rat model of isolated limb infusion. Experimental Design: Athymic rats bearing s.c. human melanoma xenografts (DM6) in their hind limbs were randomized to a 15-minute isolated limb infusion procedure with or without temozolomide at room temperature, normothermic (37.5jC), or hyperthermic (43jC) conditions. Results: The concomitant administration of hyperthermia during an infusion with temozolomide led to the greatest increase in tumor growth delay, decreased proliferative index, and increased cell death. Isolated limb infusion treatment with a low dose (350 mg/kg) of temozolomide was ineffective at producing tumor growth delay (P = 0.07). Similarly, temozolomide infusion under normothermia yielded minimal tumor growth delay (P = 0.08). In contrast, the combination of hyperthermia plus temozolomide treatment produced marked tumor growth delay of 10.4 days (P = 0.02) with minimal toxicity. The addition of heat to temozolomide treatment yielded the smallest proliferative index (P = 0.001), while markedly increasing the level of apoptosis 48 hours after isolated limb infusion. Conclusion: This study, the first to examine the interaction between hyperthermia and temozolomide, shows a strong, synergistic antitumor effect when hyperthermia is combined with temozolomide for regional treatment of melanoma confined to an extremity. The mechanism of this synergy seems to be through an augmentation, by hyperthermia, of the antiproliferative and proapoptotic effects of temozolomide. Isolated limb perfusion and isolated limb infusion haveemerged as effective forms of treatment for regionally advanced melanoma confined to an extremity. These procedures address all in-transit lesions confined to an extremity in a single procedure by supplying a regional concentration of chemotherapeutic agents at least 10 times higher than that reached after systemic administration, without the systemic side effects.Hyperthermia is widely used in conjunction with isolated limb perfusion and infusion to improve the response to the regional chemotherapy. This is usually done by heating the perfusate (or infusate) to 39jC to 41jC and by applying external warming blankets to prevent heat loss. Hyperthermic isolated limb perfusion was introduced based on in vitro evidence of a synergistic, cytotoxic interaction between heat and melphalan, the alkylating agent that is the current drug of choice for regional therapy of melanoma (1). Melphalan has been extensively studied for its efficacy in hyperthermic isolated limb perfusion, with response rates in the 80% range with 40% to 80% being complete responders (2, 3).However, a recent,...

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“…The drug was not removed after application as the half-life of temozolomide and the first derivative MTIC is about 2 h (Kim et al, 1997).…”

Section: Proliferation Assaymentioning

confidence: 99%

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

et al. 2003

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Temozolomide is an alkylating cytostatic drug that finds increasing application in the treatment of melanoma, anaplastic astrocytoma and glioblastoma multiforme. The compound is a prodrug that decomposes spontaneously, independent of an enzymatic activation step. DNA methylation induces futile mismatch repair cycles and depletion of the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase should then initiate programmed cell death. We show drug-dependent inhibition of tumour growth in a threedimensional cell culture model of the glioma cell lines U87MG and GaMG. Migrational behaviour of the glioblastoma cells remained unaltered. However, coincubation of tumour spheroids with primary brain aggregates showed reduced tumour cell invasion into brain tissue in the presence of temozolomide. This was not achieved by slowing cellular migration, as temozolomide-treated cells displayed no reduced motility. By transferase-mediated dUTP nick-end labelling (TUNEL) of apoptotic nuclei, we found that the drug was able to induce apoptosis throughout the tumour cell spheroids. Apoptosis was highest in the core region of the spheroids. Repetitive application of sublethal doses of temozolomide to multicellular spheroids resulted in the development of drug resistance in GaMG cells. We suggest that temozolomide is a strong initiator of apoptosis in glioblastoma tumour cells in a spheroid cell culture system, when cells are already in a stressful environment.

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High-performance liquid chromatographic determination and stability of 5-(3-methyltriazen-1-yl)-imidazo-4-carboximide, the biologically active product of the antitumor agent temozolomide, in human plasma

Cited by 39 publications

References 10 publications

Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma

Efficacy of temozolomide or dacarbazine in combination with an anthracycline for rescue chemotherapy in dogs with lymphoma

Optimizing a Novel Regional Chemotherapeutic Agent against Melanoma: Hyperthermia-Induced Enhancement of Temozolomide Cytotoxicity

Temozolomide induces apoptosis and senescence in glioma cells cultured as multicellular spheroids

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