칼리케아미신감마(1)I

그림문자(GHS)

• 그림문자(GHS)

  

• 신호 어

  Danger

• 유해·위험 문구

  H302：삼키면 유해함

  H341：유전적인 결함을 일으킬 것으로 의심됨 (노출되어도 생식세포 유전독성을 일으키지 않는다는 결정적인 증거가 있는 노출경로가 있다면 노출경로 기재)

  H361：태아 또는 생식능력에 손상을 일으킬 것으로 의심됨

  H372：장기간 또는 반복 노출되면 장기(또는, 영향을 받은 알려진 모든 장기를 명시)에 손상을 일으킴

• 예방조치문구

  P201：사용 전 취급 설명서를 확보하시오.

  P202：모든 안전 조치 문구를 읽고 이해하기 전에는 취급하지 마시오.

  P260：분진·흄·가스·미스트·증기·...·스프레이를 흡입하지 마시오.

  P264：취급 후에는 손을 철저히 씻으시오.

  P264：취급 후에는 손을 철저히 씻으시오.

  P270：이 제품을 사용할 때에는 먹거나, 마시거나 흡연하지 마시오.

  P281：요구되는 개인 보호구를 착용하시오

  P301+P312：삼켜서 불편함을 느끼면 의료기관(의사)의 진찰을 받으시오.

  P308+P313：노출 또는 접촉이 우려되면 의학적인 조치· 조언를 구하시오.

  P314：불편함을 느끼면 의학적인 조치·조언을 구하시오.

  P330：입을 씻어내시오.

  P405：밀봉하여 저장하시오.

  P501：...에 내용물 / 용기를 폐기 하시오.

칼리케아미신감마(1)I 화학적 특성, 용도, 생산

• 역사

  calicheamicin gamma has been proposed that Alexander the Great was poisoned by drinking the water of the river Mavroneri (identified with the mythological River Styx) which is postulated to have been contaminated by this compound. However, toxicologists believe an extensive knowledge of biological chemistry would have been requisite for any application of this poison in antiquity.

• 용도

  Calicheamicins are a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora, The main component is calicheamicin γ1. It has strong anti-Gram-positive bacteria activity and anti-tumor effect.

• 생물학적 활성

  Calicheamicin γ1 is an enediyne antitumor antibiotic that acts by binding to DNA and causes strand scission; ADC payload used in development of antibody drug conjugates.

• Mechanism of action

  Calicheamicins target DNA and cause strand scission. Calicheamicins bind with DNA in the minor groove, wherein they then undergo a reaction analogous to the Bergman cyclization to generate a diradical species. This diradical, 1,4-didehydrobenzene, then abstracts hydrogen atoms from the deoxyribose (sugar) backbone of DNA, which ultimately leads to strand scission.The specificity of binding of calicheamicin to the minor groove of DNA was demonstrated by Crothers et al. (1999) to be due to the aryltetrasaccharide group of the molecule.

• in vitro

  PF-06647263 (anti-EFNA4-ADC) is generated via conjugation of hE22 lysine residues to the AcButDMH-N-Ac-calicheamicin-γ1 linker-payload with an average drug-to-antibody ratio (DAR) of 4.6. PF-06647263 elicits antigen- and concentration-dependent cytotoxicity, as exposure to PF-06647263 for 96 hours results in cell death (EC 50 = appr 1 ng/mL). CMC-544, consisting of a humanized CD22 Ab linked to calicheamicin, is effective in pediatric primary B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells in vitro. CMC-544 induces cell death in various ALL cell lines in a dose- and time-dependent way, with IC 50 values ranging from 0.15 to 4.9?ng/mL. CMC-544 (10?ng/mL) is effective and specific in primary BCP-ALL cells. In CMC-544-treated cells, the level of CD22 has decreased relative to that on G5/44-treated cells and continued to decrease.

• in vivo

  An ADC comprising a humanized anti-EFNA4 monoclonal antibody conjugated to the DNA-damaging agent calicheamicin achieves sustained tumor regressions in both TNBC and ovarian cancer PDX in vivo. PF-06647263 (0.27, 0.36 mg/kg) results in significant tumor regressions in TNBC xenografts.

• target

  Calicheamicins

• 참고 문헌

  [1] Huryn, D. and P. Wipf. “CHAPTER 5 – Natural product chemistry and anticancer drug discovery.”Cancer Drug Design and Discovery (2008) 107-130.
  [2] Berova, N. G. Ellestad and N. Harada. “Characterization by Circular Dichroism Spectroscopy.”Comprehensive Natural Products II (2010): 91-146.

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