20-<i>O</i>-Acylcamptothecin Derivatives:  Evidence for Lactone Stabilization

Zhao, Hong; Lee, Chyi; Sai, Prakash; Choe, Yun H.; Boro, Michelle; Pendri, Annapurna; Guan, Shuiyun; Greenwald, Richard B.

doi:10.1021/jo000221n

Cited by 153 publications

(121 citation statements)

References 23 publications

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“…An additional benefit of CPT conjugation is stabilization of the active lactone form to higher pH values (19). Conjugate concentrations in Table 1 and future discussions refer to the free drug equivalent concentration of the conjugate.…”

Section: Resultsmentioning

confidence: 99%

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

2007

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Controlled release of chemotherapy drugs from polymer implants placed directly at the tumor site is a proven method for treatment of cancers of the brain. Although this method provides high doses of drug at the tumor site, the drug does not penetrate far enough into the brain for optimum treatment in most cases. Rapid drug elimination leads to more than a 10-fold drop in concentration within 2 mm of the implant. Conjugation to water-soluble polymers, such as poly(ethylene glycol) (PEG) or dextran, has the potential to increase drug distribution in the brain. We have recently PEGylated the chemotherapy drug camptothecin and found a large increase in the extent of distribution of camptothecin in the rat brain, but most of the drug in tissue was in the less-active conjugated form. Stability of the conjugation bond, activity of the drug-polymer conjugate, solubility of the conjugate relative to the drug, and molecular weight of the polymer must all be considered in the design of a conjugate to maximize drug distribution. Therefore, to optimize the PEGylated system, we have developed a pharmacokinetic model to determine the relative importance of parameters involved in the distribution of drug-polymer conjugates after release from a polymer implant. Our modeling shows that PEGylation has the potential to increase treatment distances to more than a centimeter, which may be sufficient to prevent the recurrence of human brain tumors.

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Section: Resultsmentioning

confidence: 99%

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

2007

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“…Studies with irinotecan have shown the carboxylate form of SN-38 is only 10% as potent as the lactone form (49). The CL2A-linked SN-38 is derivatized at the 20-hydroxyl position, a process that stabilizes the lactone group in camptothecins under physiologic conditions (50). Because the in vitro stability studies and the analysis of serum stability were conducted under acidic conditions, we do not have a direct measure of the carboxylate form of SN-38 in either of these conjugates, but it is reasonable to suspect that destabilization of the lactone ring could have contributed to CL2E's diminished efficacy in vivo.…”

Section: Discussionmentioning

confidence: 99%

Milatuzumab–SN-38 Conjugates for the Treatment of CD74+ Cancers

Govindan

Cardillo

Sharkey

et al. 2013

Molecular Cancer Therapeutics

119

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CD74 is an attractive target for antibody-drug conjugates (ADC), because it internalizes and recycles after antibody binding. CD74 mostly is associated with hematologic tumors but is expressed also in solid cancers. Therefore, ADCs of the humanized anti-CD74 antibody, milatuzumab, were examined for the therapy of CD74-expressing solid tumors. Milatuzumab-doxorubicin and two milatuzumab-SN-38 conjugates with cleavable linkers, differing in their stability in serum and how they release SN-38 in the lysosome, were prepared. CD74 expression was determined by flow cytometry and immunohistology. In vitro cytotoxicity and in vivo therapeutic studies were conducted in the human cancer cell lines A-375 (melanoma), HuH-7 and Hep-G2 (hepatoma), Capan-1 (pancreatic), NCI-N87 (gastric), and Raji Burkitt lymphoma. The milatuzumab-SN-38 ADC was compared with SN-38 ADCs prepared with anti-Trop-2 and anti-CEACAM6 antibodies in xenografts expressing their target antigens. Milatuzumab-doxorubicin was most effective in the lymphoma model, whereas in A-375 and Capan-1 solid tumors, only milatuzumab-SN-38 showed a therapeutic benefit. Despite much lower surface expression of CD74 than Trop-2 or CEACAM6, milatuzumab-SN-38 had similar efficacy in Capan-1 as anti-Trop-2-SN-38, but in NCI-N87, anti-CEACAM6 and anti-Trop-2 conjugates were superior. Studies in two hepatoma lines at a single dose level showed significant benefit over saline controls but not against an irrelevant immunoglobulin G conjugate. CD74 is a suitable target for ADCs in some solid tumor xenografts, with efficacy largely influenced by uniformity of CD74 expression and with SN-38 conjugates providing the best therapeutic responses; SN-38 conjugates were preferable in solid cancers, whereas doxorubicin ADC was better in lymphoma tested. Mol Cancer Ther; 12(6); 968-78. Ó2013 AACR.

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“…Acylation of the (O20) lactone ring hydroxyl significantly increases the stability. 3,4 Hydrophilization of the CPT molecule results in water soluble forms, e.g., Irinotecan (CPT-11). The latter is the most widely used soluble prodrug, which (as well as other CPT prodrugs) requires endoplasmic activation, mainly in the liver, for conversion into the active form (SN38 5 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

et al. 2004

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A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t 1/2 = 2.2 ± 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t 1/2 = 2.1 ± 0.2 h, while the conjugate half-life was 14.2 ±1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.

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20-O-Acylcamptothecin Derivatives: Evidence for Lactone Stabilization

Cited by 153 publications

References 23 publications

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

Conjugation to Increase Treatment Volume during Local Therapy: A Case Study with PEGylated Camptothecin

Milatuzumab–SN-38 Conjugates for the Treatment of CD74+ Cancers

Synthesis of a Macromolecular Camptothecin Conjugate with Dual Phase Drug Release

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