Carboxypeptidase G2 rescue after high-dose methotrexate.

DeAngelis, Lisa M.; Tong, William P.; Lin, Shiuan-Pey; Fleisher, Martin; Bertino, Joseph R.

doi:10.1200/jco.1996.14.7.2145

Cited by 60 publications

(46 citation statements)

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“…Nevertheless, a diminished effect of repeated CPG2 administration in reduction of MTX levels has been demonstrated in these animals [24]. DeAngelis et al [25] were also able to detect CPG2 antibody in 1/4 patients. Moreover, IgG and IgM antibodies to CPG2 were detected in all patients treated with ADEPT and who received no cyclosporin after 10 days [41].…”

Section: Pharmacokinetics and Toxicitymentioning

confidence: 82%

“…It has no known mammalian analogue and therefore confers high specificity for appropriate substrates but has the disadvantage of being immunogenic [41]. It is therefore not surprising that antibodies against CPG2 have been detected in animals and humans [23,25]. In the single study of ADEPT therapy using CPG2 at higher doses, all patients developed IgM and IgG antibodies except those treated with cyclosporine.…”

Section: Discussionmentioning

confidence: 99%

“…The t 1/2 in the CSF was 3.6 h in rhesus monkeys [24]. CPG2 was not detected in the CSF after intravenous administration in humans [25]. Given intravenously, CPG2 is able to reduce MTX plasma levels 100-fold within 15 min.…”

Section: Pharmacokinetics and Toxicitymentioning

confidence: 97%

“…In several clinical studies DAMPA accumulated after CPG2 administration [25,27]. Its t 1/2 ranged between 4.9 and 49.5 h. This substance is much less toxic but also less soluble at an acid pH than MTX.Thus, there may be an additional risk for nephrotoxicity caused by precipitating DAMPA in acidic urine and patients still require additional alkalinization after HD-MTX and CPG2 rescue.…”

Section: Pharmacokinetics and Toxicitymentioning

confidence: 99%

“…With the availability of recombinant CPG2, there have been several small series of patients receiving MTX rescue by CPG2. CPG2 was studied in 4 patients with primary CNS lymphoma [25]. These patients received 3 g/m 2 body surface area MTX over 2 h. 12 h after MTX infusion, CPG2 (50 U/kg body weight) was administered intravenously.…”

Section: Carboxypeptidase G2 and Mtx Rescuementioning

confidence: 99%

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Targeting Folates by Carboxypeptidase G2: Potential Applications in Anticancer Therapy

Krackhardt

Schwartz²,

Thiel³

2000

Oncol Res Treat

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Carboxypeptidase G2 (CPG2) cleaves folates and folate analogues resulting in alternative routes of folate metabolism. CPG2 is of particular interest in anticancer therapy for several reasons. CPG2 rapidly converts methotrexate (MTX) into less toxic metabolites causing a rapid decline of MTX serum levels in animal models as well as in humans. Thus, CPG2 is a powerful rescue agent in patients receiving high-dose MTX and might circumvent life-threatening toxicity in patients with MTX intoxication. As CPG2 causes a predefined and considerable decline of MTX levels, this substance might be also attractive for MTX dose escalation studies. In addition, CPG2 has been used in antibody-directed enzyme prodrug therapy. Prodrugs have been developed which are cleaved by CPG2, resulting in a release of active cytotoxic agents. The use of these prodrugs, attached to a tumor-specific antibody-CPG2- complex, might enhance concentrations of cytotoxic drugs in tumor tissues. Finally, CPG2 has been investigated in combination with trimetrexate, as it has been shown that trimetrexate is resistant to CPG2 cleavage. In conclusion, CPG2 is a novel drug with promising properties. However, clinical experiences are limited and further studies are necessary to define the role of CPG2 in cancer therapy.

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Section: Pharmacokinetics and Toxicitymentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Pharmacokinetics and Toxicitymentioning

confidence: 97%

Section: Pharmacokinetics and Toxicitymentioning

confidence: 99%

Section: Carboxypeptidase G2 and Mtx Rescuementioning

confidence: 99%

See 3 more Smart Citations

Targeting Folates by Carboxypeptidase G2: Potential Applications in Anticancer Therapy

Krackhardt

Schwartz²,

Thiel³

2000

Oncol Res Treat

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Characterisation of the Carboxypeptidase G2 Catalytic Site and Design of New Inhibitors for Cancer Therapy

et al. 2018

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The enzyme carboxypeptidase G2 (CPG2) is used in antibody-directed enzyme prodrug therapy (ADEPT) to catalyse the formation of an active drug from an inert prodrug. Free CPG2 in the bloodstream must be inhibited before administration of the prodrug in order to avoid a systemic reaction in the patient. Although a few small-molecule CPG2 inhibitors have been reported, none has been taken forward thus far. This lack of progress is due in part to a lack of structural understanding of the CPG2 active site as well as the absence of small molecules that can block the active site whilst targeting the complex for clearance. The work described here aimed to address both areas. We report the structural/functional impact of extensive point mutation across the putative CPG2 catalytic site and adjacent regions for the first time, revealing that residues outside the catalytic region (K208A, S210A and T357A) are crucial to enzyme activity. We also describe novel molecules that inhibit CPG2 whilst maintaining the accessibility of galactosylated moieties aimed at targeting the enzyme for clearance. This work acts as a platform for the future development of high-affinity CPG2 inhibitors that occupy new chemical space and will advance the safe application of ADEPT in cancer treatment.

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Resumption of high‐dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients

Christensen

Pauley

Molinelli

et al. 2012

Cancer

104

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Background High-dose methotrexate (HDMTX)-induced acute kidney injury is a rare but life-threatening complication. The methotrexate rescue agent glucarpidase rapidly hydrolyzes methotrexate to inactive metabolites. We retrospectively reviewed glucarpidase use in pediatric cancer patients at our institution and evaluated whether subsequent resumption of HDMTX was tolerated. Methods Clinical data and outcomes of all patients who received glucarpidase after HDMTX administration were reviewed. Results Of 1,141 patients treated with 4,909 courses of HDMTX, 20 patients (1.8% of patients, 0.4% of courses) received 22 doses of glucarpidase. The median glucarpidase dosage was 51.6 units/kg (range, 13 – 65.6 units/kg). At the time of administration, the median plasma methotrexate concentration was 29.1 µM (range, 1.3 – 590.6 µM). Thirteen of the 20 patients received a total of 39 courses of HDMTX therapy after glucarpidase. The median time to complete methotrexate excretion was 355 hours (range, 244 – 763 hours) for the HDMTX course during which glucarpidase was administered, 90 hours (range, 66 – 268 hours) for the next HDMTX course, and 72 hours (range, 42 – 116 hours) for subsequent courses. The median peak serum creatinine during these HDMTX courses was 2.2 mg/dL (range, 0.8 – 9.6 mg/dL), 0.8 mg/dL (range, 0.4 – 1.6 mg/dL), and 0.6 mg/dL (range, 0.4 – 0.9 mg/dL), respectively. One patient experienced nephrotoxicity upon rechallenge with HDMTX. Renal function eventually returned to baseline in all patients and no patient died as a result of methotrexate toxicity. Conclusion It is possible to safely resume HDMTX therapy after glucarpidase treatment for HDMTX-induced acute kidney injury.

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Carboxypeptidase G2 rescue after high-dose methotrexate.

Abstract: CPG2 rescue is a safe, effective alternative to leucovorin rescue after HD MTX and may prove particularly useful for the treatment of MTX-sensitive CNS tumors, as it does not affect CSF MTX levels.

Cited by 60 publications

References 0 publications

Targeting Folates by Carboxypeptidase G2: Potential Applications in Anticancer Therapy

Targeting Folates by Carboxypeptidase G2: Potential Applications in Anticancer Therapy

Characterisation of the Carboxypeptidase G2 Catalytic Site and Design of New Inhibitors for Cancer Therapy

Resumption of high‐dose methotrexate after acute kidney injury and glucarpidase use in pediatric oncology patients

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