Anti-cancer drug design
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Anti-cancer drug design · Dec 2001
The inhibition of protein phosphatases 1 and 2A: a new target for rational anti-cancer drug design?
Recent investigations in our laboratories have highlighted that the inhibition of the serine/threonine protein phosphatases 1 and 2A (PP1 and PP2A) is an excellent target for the development of novel anti-cancer agents. Using a combination of the known crystal structure of PP1 and the modelled structure of PP2A, we have rationally designed a new class of protein phosphatase inhibitors, cantharimides, which exhibit broad-spectrum anti-cancer activity. Synthetic modifications of the simplest known PP1 and PP2A inhibitor, norcantharidin, has led to the development of potent PP1 and PP2A inhibitors.
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Anti-cancer drug design · Dec 1998
Synthesis of self-immolative glucuronide-based prodrugs of a phenol mustard.
The design and synthesis of the mustard pro-prodrugs which can be used in ADEPT is reported. Prodrugs 1 and 2 include a glucuronide group which is connected to the drug via an aromatic and/or aliphatic bis-carbamate spacer. The design of these new prodrugs takes advantage of a spontaneous 1,6-elimination and/or an intramolecular cyclization reaction after enzymatic cleavage. ⋯ According to in vitro experiments, prodrugs 1 and 2 were approximately 50- and 80-fold less cytotoxic than the parent drug and, when treated with beta-glucuronidase, the level of cytotoxic activity of 1 became comparable to that of the drug. Stability of 1 in phosphate buffer was satisfactory. These results demonstrate that 1 is a prodrug that can be specifically activated to release the cytotoxic agent.
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Anti-cancer drug design · Jan 1998
Chemical, biochemical and pharmacological activity of the novel sterically hindered platinum co-ordination complex, cis-[amminedichloro(2-methylpyridine)] platinum(II) (AMD473).
cis-[Amminedichloro(2-methylpyridine)] platinum(II) (AMD473) is a novel sterically hindered anti-tumour compound designed to circumvent platinum drug resistance and is due to begin clinical trials in 1997. This paper reports the rationale behind the development of AMD473 with regard to its chemical and DNA binding properties. AMD473 circumvents resistance in vitro in acquired cisplatin resistant human ovarian carcinoma (HOC) cell line models (2 h SRB assay mean resistance factor = 2.8 +/- 1.2 microM for AMD473, versus 6.5 +/- 3.5 microM for cisplatin). ⋯ As steric hindrance was increased from AMD494 (unsubstituted pyridine) through AMD473 to AMD508 (2,6-dimethylpyridine), by addition of methyl groups on the pyridine ligand, cross-link formation rates became slower. By alkaline elution, at equimolar doses, AMD473 ICL formation after 24 h incubation was less than that of cisplatin after 4 h. Understanding the chemical and biochemical properties of these sterically hindered platinum complexes may aid the development of more novel platinum chemotherapeutic agents capable of further improving anti-tumour activity in resistant tumours.
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Anti-cancer drug design · Jan 1998
Antitumor activity of a PKC-alpha antisense oligonucleotide in combination with standard chemotherapeutic agents against various human tumors transplanted into nude mice.
A 20-mer phosphorothioate oligodeoxynucleotide (ODN) directed against human protein kinase C-alpha (CGP 64128A = ISIS 3521) was analyzed for its antitumor activity either alone or in combination therapy. Combination studies with CGP 64128A and standard chemotherapeutic agents (cisplatin, mitomycin-C, vinblastine, estracyt and adriamycin) were performed in nude mice that had been transplanted s.c. with a variety of human tumors (breast, prostate, large cell lung and small cell lung carcinomas, and melanomas). Additive antitumor effects with CGP 64128A and the cytotoxins were found for half of the combinations studied. ⋯ CGP 64128A in combination with adriamycin resulted in superadditive antitumor effects against BT20 human breast carcinomas with complete tumor responses, and in combination with mitomycin-C superadditive antitumor effects with cures were observed against NCI-H460 human large cell carcinomas. The antitumor activity of CGP 64128A appeared to be due to a sequence-dependent mechanism of action as two 20-mer control ODNs were completely inactive as single agents against A549 and NCI-H69 human lung carcinomas. The antitumor activity of cisplatin against NCI-H69 human small cell lung carcinomas was slightly inhibited by one of the control ODNs, indicating that the superadditive antitumor activities of CGP 64128A in combination with cisplatin are the result of a sequence-dependent mechanism of action.
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Anti-cancer drug design · Mar 1997
Saporin 6 and lonidamine in primary cell cultures from human breast carcinomas: a synergistic effect.
Lonidamine (LND) is a potential chemotherapeutic agent which can positively modulate the efficacy of several antineoplastic agents. The ribosome-inactivating protein Saporin 6 (SO 6), which acts as a rRNA N-glycosidase and a DNA nuclease, has recently attracted interest as a novel potential anticancer and antiviral agent. Synergism between LND and SO 6 was previously demonstrated by us in the human metastatic MAST breast cancer cell line in vitro. ⋯ Results indicate a strong synergistic effect in 11/17 cases, when LND was administered as a second drug. This is in agreement with previous results in the MAST cell line. Synergism was evident at SO 6 concentrations between 3.3 x 10(-10) and 1.7 x 10(-9) M.