Lastet Mechanism of Action

Pharmacology: Antitumor activity: Antitumor activity was observed against the following tumors: L1210 murine tumor and P388 leukemia, B16 melanoma, Lewis lung cancer, colon tumor 26, colon tumor 38, M5076 ovarian cancer and Ehrlich's carcinoma. In addition, antitumor activity was also recognized against the AH66F and AH66 lines of rat ascites hepatoma.
Mechanism of Action: Etoposide exhibits cytocidal activity against cells in the late S and G₂ phase of the cell cycle, and blocking the G₂ phase. Its mechanism of action is believed to be through the indirect induction of the scission of the DNA chain without directly acting on it. In addition, the cytocidal action is enhanced according to both administration time dependently and administration concentration dependently.
Clinical Studies: The following is a summary of the clinical results of the oral administration of etoposide as a single agent in the patients of small cell lung cancer and malignant lymphoma.
Clinical Effect: The response rate in the area of small cell lung cancer is 33/128=25.8%, and the remission rate in the area of malignant lymphoma is 38/92=41.3%.
Adverse Reactions, including changes in laboratory values: Adverse reactions out of 1,614 cases evaluable for side effects included alopecia (32.4%), anorexia (27.7%), nausea (20.4%), vomiting (9.6%), diarrhea (3.0%), stomatitis (5.9%), general malaise (9.1%), fever (4.8%).
Abnormalities in laboratory values were mainly related to myelosuppression such as leucopenia (47.2%), erythrocytopenia (30.2%) and thrombocytopenia (19.8%). Further, abnormalities in tests related to hepatic function such as elevation in GOT (7.3%), GPT (7.5%), Al-P (3.2%), γ-GTP (3.0%), as well as abnormalities in tests related to renal function such as elevation of BUN (2.9%) were also observed.
Pharmacokinetics: Blood Concentration and Urinary Excretion: The serum concentration in cancer patients given a single dose of the drug reached the peak value 1-2 hours after administration, and then gradually decreased. The rate of urinary excretion of the unchanged drug up to 24 hours after administration was 6-30% of the dose. (See figure.)

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Further, in the study administering 5 consecutive daily doses orally to cancer patients, no significant differences in blood level of etoposide were observed between the group given 200 mg/body/day once in the morning and the group given 200 mg/body/day in two divided doses, once in the evening and once in the morning, and no accumulation tendencies were observed.
Toxicology: Non-Clinical Studies: Toxicity: Single dose toxicity (LD₅₀ mg/kg): See table.

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Repeated dose toxicity: The results of the subacute and chronic toxicity studies via both the oral and i.v. routes in rats and dogs show that the major target organs for toxicity are the hematopoietic system (anemia, hypoplasia of bone marrow, atrophy of splenic germinal centers, decrease in leukocyte and erythrocyte counts), the lymphatic system (atrophy of the thymus and the lymphnodes), the male genital organs (atrophy of the testicles and the epididymis), and gastrointestinal symptoms during oral administration (diarrhea and intestinal bleeding). All abnormalities except those seen in the male genital organs were reversible on cessation of administration.
Reproductive and developmental toxicity: In the study involving rats dosed during the pregestation and early gestation periods, the major changes noted were a decrease in the number of implantations, an increase in the number of resorptions of the fetus and depending on dose, teratogenicity (ophthalmic and cephalic abnormalities). In the study involving administration during the organogenetic period, fetal toxicity such as fetal death and delayed growth, teratogenicity (ophthalmic and cephalic abnormalities), post-natal delayed growth, inhibited development of genital organs along with hypoplasia of genital organs in live offspring were observed. In the study involving administration of the drug during the organogenetic period of rabbits, fetal toxicity mainly involving fetal death and delayed growth along with teratogenicity (visual abnormalities, etc.) were observed varying with administrative route and dose. Further, in the study involving administration of the drug during the prenatal and nursing periods of rats, major changes noted involved prenatal fetal toxicity such as prenatal death, postnatal delayed growth, inhibited development of genital organs and hypoplasia of genital organs.
Other Toxicities: Etoposide was recognized to be mutagenic as a result of Rec-assay involving Bacillus subtilis H17 rec⁺ and M45 rec^-, the Reverse Mutation Test involving Salmonella typhimurium T98, T1537 and T1538, and in the Micronucleus Test employing mice.
Distribution and Excretion in Animals: Blood Concentration (Rat, Dog): In rats, after blood levels reached the peak value 2 hours after administration, the blood levels decreased biphasically with the half-life (t_½) being 3.5 hours in the α-phase and 36.5 hours in the β-phase. In dogs, after blood levels reached the peak value 1 hour after administration, the blood levels decreased biphasically with the half-life (t_½) being 1.8 hours in the α-phase, 30.8 hours in the β-phase.
Distribution (Rat): After distribution of the substance in the liver, kidneys, bladder, mesenteric lymph nodes, adrenals and lungs, the levels decreased rapidly.
Excretion (Rat, Dog): For rats 72 hours after administration, 7.2% of the substance was excreted in the urine and 87.2% excreted in the feces. In addition, for dogs 72 hours after administration, 4.3% was excreted in the urine and 81.7% was excreted in the feces.