Anti-tumor effects of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate.

Senter, Peter D.; Saulnier, Mark G.; Schreiber, George J.; Hirschberg, David L.; Brown, Joseph P.; Hellström, Ingegerd; Hellström, Karl Erik

doi:10.1073/pnas.85.13.4842

Cited by 205 publications

(115 citation statements)

References 13 publications

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“…AP in the bile was found to be responsible for this phenomenon. The latter conclusion of the present study is based on indirect evidence, but others have shown that etoposide is rapidly converted to etoposide by AP in vitro (Senter et al, 1988).…”

Section: Discussionmentioning

confidence: 45%

Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile

Dejong

Slijfer²,

Uges³

et al. 1997

Br J Cancer

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Summary Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that this prodrug could be used to overcome the solubility limitations and erratic bioavailability of oral etoposide. To investigate the possibility of prodrug conversion to etoposide within the gastrointestinal lumen, etoposide phosphate was dissolved in water and incubated with human gastric juice or human bile in vitro. Samples were collected during 150 min and analysed for etoposide concentration with high-performance liquid chromatography. Conversion of prodrug to etoposide during incubation with gastric juice was negligible. There was significant conversion during incubation with bile at pH 7-8. The percentage of prodrug converted to etoposide at pH 8 after 60 min was 78 ± 18% (mean ± S.D.) for a 0.1 mg ml-' prodrug solution and 36 ± 26% for 0.5 mg ml-'. At pH 7, after 60 min 22% of prodrug was converted to etoposide when incubated at 0.1 mg ml-' and 10% at 0.5 mg ml-'. No conversion was found after inactivation of alkaline phosphate (AP) by overnight heating of bile at 650C or by the addition of disodium edetate to the bile. In conclusion, because of AP in bile, variable conversion of etoposide phosphate to etoposide can be expected within the intestinal lumen after oral administration. This could have important pharmacokinetic consequences.

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Section: Discussionmentioning

confidence: 45%

Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile

Dejong

Slijfer²,

Uges³

et al. 1997

Br J Cancer

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“…Enzymic activation of a less cytotoxic prodrug in the vicinity of the target cells has been demonstrated to lead to increased therapeutic efficacy. An example is the enhanced effect of antibody-alkaline phosphatase conjugate of etoposide phosphate both in vitro and in vivo (97).…”

Section: Immunotoxinsmentioning

confidence: 99%

Monoclonal antibodies in drug targeting

Panchagnula

Dey

1997

Journal of Clinical Pharmacy and Therapeutics

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SUMMARYThe objective of drug targeting is to deliver drugs to a specific site of action through a carrier system. In cancer chemotherapy, cytotoxic drugs kill cancerous cells but also damage normal cells. Monoclonal antibodies generated against specific antigens, when conjugated to cytotoxic drugs, can selectively deliver drugs to cancer cells while minimizing damage to normal cells. Of all the carrier systems available, monoclonal antibodies are gaining importance because of their high specificity. The purpose of this review is to provide a comprehensive account of the use of monoclonal antibodies in drug targeting, highlighting their scope and limitations.

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“…Monoclonal antibodies can also be used for tumour-selective delivery of an enzyme that converts a relatively non-toxic prodrug into its toxic drug. This approach is called antibody-directed enzyme prodrug therapy (ADEPT) (Bagshawe, 1987;Senter et al, 1988). The idea of using antibodies to localize enzymes to the tumour was originally conceived by Philpott et al (1973).…”

mentioning

confidence: 99%

A fully human anti-Ep-CAM scFv-beta-glucuronidase fusion protein for selective chemotherapy with a glucuronide prodrug

et al. 2002

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Monoclonal antibodies against tumour-associated antigens could be useful to deliver enzymes selectively to the site of a tumour for activation of a non-toxic prodrug. A completely human fusion protein may be advantageous for repeated administration, as host immune responses may be avoided. We have constructed a fusion protein consisting of a human single chain Fv antibody, C28, against the epithelial cell adhesion molecule and the human enzyme b-glucuronidase. The sequences encoding C28 and human enzyme b-glucuronidase were joined by a sequence encoding a flexible linker, and were preceded by the IgGk signal sequence for secretion of the fusion protein. A CHO cell line was engineered to secrete C28-bglucuronidase fusion protein. Antibody specificity and enzyme activity were retained in the secreted fusion protein that had an apparent molecular mass of 100 kDa under denaturing conditions. The fusion protein was able to convert a non-toxic prodrug of doxorubicin, N-

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Anti-tumor effects of antibody-alkaline phosphatase conjugates in combination with etoposide phosphate.

Abstract: Two anti-tumor monoclonal antibodies, LX (anticarcinoma) and 1F5 (anti-B lymphoma), were

Cited by 205 publications

References 13 publications

Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile

Conversion of the prodrug etoposide phosphate to etoposide in gastric juice and bile

Monoclonal antibodies in drug targeting

A fully human anti-Ep-CAM scFv-beta-glucuronidase fusion protein for selective chemotherapy with a glucuronide prodrug

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