Pre-clinical trials

* Purpose of pre-clinical trials – Study the on safety, effectiveness, and toxicity of test material “TetraAs (As4O6)”
* Testing institute of pre-clinical triasl – Biotoxtech, Korea Cancer Center Hospital, China *** medical research institute
* Period of pre-clinical trials – 2001 ~ 2007, 2014 ~ 2016

Efficacy and Effectiveness

ANTI
ANGIOGENESIS

CONTENTS OF STUDY >

  • To identify anti-angiogenesis effect and mechanism using endothelial cells
  • To identify systemic anti-angiogenesis effect using rats

RESULTS >

  • Identified inhibition of proliferation, migration, infiltration, and angiogenesis through in vitro study.
  • Identified significant inhibition of systemic angiogenesis in in vivo experiment
  • No death, weight loss, evacuation disorder, motor disorder, and abnormal behavior of experimental animals were observed

APOTOSIS

CONTENTS OF STUDY >

  • To identify mechanism and effect of apoptosis of cancer cells

RESULTS >

  • Identified mechanism and effect of apoptosis of cancer cells
  • Confirmed apoptotic function of cancer cells including blood cancer, liver cancer, and bladder cancer.
Toxicology and Pharmacokinetics

TOXICITY

CONTENTS OF STUDY >

  • Toxicity of dose once a day
  • Toxicity of repetitive dose for 13 weeks
  • Toxicity of repetitive dose for 26 weeks
  • Toxicity of repetitive dose for 52 week
  • Genetic toxicity (chromosome abnormality, mutation, micronucleus test)

RESULTS >

  • Almost no adverse toxicity effect from single and repetitive dose
  • No chromosomal abnormality

PHARMACOKINETICS

CONTENTS OF STUDY >

  • Pharmacokinetic Study on ADME (absorption, distribution, metabolism, excretion) course

RESULTS >

  • Peak plasma concentration occurred at about 2 hours after oral administration
  • Good distribution to tissues and organs
  • High excretion in feces
  • Absolute cumulative contribution ratio increased slowly from 48.3, 57.3, to 65.3% for 1, 2, and 3 weeks of repetitive oral administration and decreased rapidly for the 1st week and then slowly for 1 to 2 weeks of recovery period after the termination of administration

Antiangeogenesis effect of As4O6

01. Experiment on the cornea of rats

EXPERIMENT

CORNEA OF RATS

(Source; J Vet Med Sci. 66:1091-5, 2004)

CASE REVIEW

22_preClinical_0726_01
22_preClinical_0726_02

As2O3(Arsenic trioxide )

22_preClinical_0726_03

As4O6 (Arsenic hexaoxide)

RESULTS

The number, length, clock hour of neovascularization and areas of the vessels in As4O6 group showed more significant inhibition than those of control and As2O3 groups from day 5

02. Vascular Endothelial Cells

EXPERIMENT

Tube forming assay With HUVEC (Vascular Endothelial Cells)

(Source; Int J Oncol; 22(6):1271-6, 2003)

CASE REVIEW

22_preClinical_0726_04
22_preClinical_0726_05

1 Micrometer => As2O3

22_preClinical_0726_06

1 Micrometer => As4O6

RESULTS

It was found that antiangiogenesis effect of vascular endothelial cells administered with As4O6 were better than that of As2O3.

(Melanoma) Lung Metastasis Case Study

EXPERIMENT

Experimental Melanoma Lung Metastasis Study

CASE REVIEW

22_preClinical_0726_07

Control

Inject B16F10 melanoma cells into
the tail vein of C57BL/6 mice
(7.5×104 cells/animal)

22_preClinical_0726_08

As4O6 Treated

Oral administration of As4O6
after the tumor inoculation and
the number of lung nodules was
counted 22 days later
(9 mice were used for the control
group and 10 mice for the
treatment group)

RESULTS

* The number of lung nodules
Control group: 93.1 +-6.3
As4O6 Treated: 39.4 +-6.3
As4O6 Treated represents 54% reduction in the tumor number

LD50 ; Male SD rat, 150 – 180 mg/Kg,
Female SD rat, 120 – 150 mg/Kg
LD50 ; Male Dog, 350 – 500mg/Kg,
Female Dog , 400 – 550mg/Kg

Enhancement of anti-cancer effect in combination therapy with conventional treatment for cancer

It was identified that the cancer therapeutic effect of TetraAs was remarkably enhanced in combination therapy with radiation and chemotherapy

Test results of combination cancer therapy of TetraAs and radiation

* Source: Korea Cancer Center Hospital, Busan Baik Hospital

preclinical_09

* Observed the progress of tumor for 7 weeks after 1 week radiation
therapy only ⓐ and 1 week combination therapy of radiation
and TetraAs ⓑ

ⓐ The observed period, the size of tumor increased again
ⓑ Up to 7 weeks, the size of tumor was reduced or changed little (combination cancer therapy effect)

<Journal> Tetra-arsenic oxide (Tetras) enhances radiation sensitivity of solid tumors by anti-vascular effect (Cancer Letters, 2009.01.20)

Test results of combination cancer therapy of TetraAs and others

* Source: School of medicine, Catholic University of Korea

preclinical_10

22_preclinical_dotsEnhanced therapeutic effect :

<Journal> Comparison of diarsenic oxide and tetra-arsenic oxide on anti-cancer effects : Relation to the apoptosis molecular pathway (International Journal of Oncology, 2007.05.01)

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