A water soluble prodrug of a novel camptothecin analog is efficacious against breast cancer resistance protein-expressing tumor xenografts.

Abstract

PURPOSE:

Identification of a novel topoisomerase I inhibitor which shows superior efficacy and less individual variation than irinotecan hydrochloride (CPT-11).

METHODS:

A novel camptothecin analog that is effective against breast cancer resistance protein (BCRP)-positive cells was screened, and a water soluble prodrug was generated. Antitumor activity of the prodrug was examined in BCRP-positive and -negative xenografts both as a single agent and in combination with other anti-cancer drugs.

RESULTS:

A novel camptothecin analog, CH0793076, was discovered. Because CH0793076 was found to be highly lipophilic, a water soluble prodrug (TP300) was generated. TP300 is stable in an acidic solution but is rapidly converted to CH0793076 under physiological pH conditions such as in sera. This efficient prodrug activation would minimize interpatient differences in pharmacokinetic and toxicity profiles. Unlike CPT-11, TP300 does not exhibit cholinergic interaction or cause acute diarrhea at effective doses. In mouse xenograft models, TP300 showed antitumor activity against both BCRP-positive and -negative xenografts, whereas CPT-11 was less active against BCRP-positive xenografts. In addition, the effective dose range (MTD/ED(50)) for TP300 was wider than for CPT-11 and TP300 showed additive or synergistic antitumor effects in combination with other anti-cancer drugs such as capecitabine, oxaliplatin, cisplatin, bevacizumab and cetuximab.

CONCLUSION:

It is therefore expected that TP300 will provide an additional treatment option for patients who will undergo chemotherapy with camptothecins.

• Authors: Mika Endo, Masanori Miwa, Masako Ura, Hiromi Tanimura, Kenji Taniguchi, Yoko Miyazaki, Jun Ohwada, Masao Tsukazaki, Satoshi Niizuma, Takeshi Murata, Sawako Ozawa, Hitomi Suda, Kotaro Ogawa, Eitaro Nanba, Shunsuke Nagao, Nobuo Shimma, Hisafumi Yamada-Okabe
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 65 Issue 2 Pg. 363-71 (Jan 2010) ISSN: 1432-0843 [Electronic] Germany
• PMID: 19495753 (Publication Type: Journal Article)

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antineoplastic Agents
• CH 0793076
• Dipeptides
• Heterocyclic Compounds, 4 or More Rings
• Neoplasm Proteins
• Prodrugs
• TP 300
• Water
• Irinotecan
• Acetylcholinesterase
• Camptothecin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (biosynthesis)
• Acetylcholinesterase (metabolism)
• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Camptothecin (analogs & derivatives, pharmacology, therapeutic use)
• Cell Line, Tumor
• Dipeptides (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm
• Drug Synergism
• Heterocyclic Compounds, 4 or More Rings (pharmacology, therapeutic use)
• Humans
• Irinotecan
• Male
• Mice
• Mice, Nude
• Neoplasm Proteins (biosynthesis)
• Prodrugs (pharmacology, therapeutic use)
• Solubility
• Water
• Xenograft Model Antitumor Assays