Effect of Hyaluronidase on Pharmacodynamics and Pharmakokinetics of Cytostatics
In a previous publication we have shown
that hyaluronidase considerably enhanced the activity of adriamycin in
the MXT-M 3.2 breast cancer of the B6D2F1 mouse, if it was
injected subcutaneously in the vicinity of the tumor 4 h prior to the
administration of the anticancer agent. In addition, we could
demonstrate that a local combination of hyaluronidase with vinblastine
leads to cures in NMRI-nu/nu mice, bearing human malignant melanoma. By
a similar approach, Smith et al. enhanced the effect of vinblastine in
the treatment of cutaneous lesions of patients with Kaposi´s
sarcoma without adding to systemic toxicity by intralesional
hyaluronidase administration before intralesional vinblastin injection
(J. Am. Acad. Dermatol. 36, 239-242 (1997)).
Although pharmacokinetic data are
essential for selecting optimal conditions for an effective combination
of the enzyme with cytostatic drugs, studies on pharmacokinetics and
tissue distribution of hyaluronidase are very limited. Investigations
on the resorption and penetration of cytostatics into tumors in
combination with hyaluronidase are also scarce.
Our pharmacological studies are focussed on the treatment of malignant melanoma and brain tumours. Analytical investigations of a combination therapy with hyaluronidase and melphalan for malignant melanoma
showed a significant increase in the intratumoral melphalan
concentration after local s.c. injection of the drug combined with
local s.c. or i.p. administration of hyaluronidase, one hour prior to
melphalan application.
Cooperation with:
- Prof. Dr. G. Baumgartner (Klinikum der Stadt Wien, Lainz, Austria)
- Prof. Dr. A. Göpferich (Department of Pharmaceutical Technology, University of Regensburg)
- Dr. Thilo Spruss (Laboratory Animal Facilities, University of Regensburg),
Selected publications and abstracts
- K. Beckenlehner, S. Bannke, Th. Spruss, G. Bernhardt,
H. Schönenberger, W. Schiess. Hyaluronidase enhances the activity
of adriamycin in breast cancer models in vitro and in vivo. J. Cancer Res. Clin. Oncol. 118, 591 – 596 (1992).
- Th. Spruss, G. Bernhardt, H. Schönenberger, W.
Schiess. Hyaluronidase significantly enhances the efficacy of regional
vinblastine chemotherapy of malignant melanoma. J. Cancer Res. Clin. Oncol. 121, 193 – 202 (1995).
- T. Spruss, G. Bernhardt. Chemosensitivity of
malignant melanoma models: longterm complete remission after regional
hyaluronidase/vinblastine therapy. in: W. Arnold (Ed.) Immunodeficient
Laboratory Animals. Contrib. Oncol. 51. Karger, Basel, 1996, pp.
145-150.
- I.
Muckenschnabel, G. Bernhardt, Th. Spruß, A. Buschauer, A
versatile HPLC method for the measurement of melphalan tailored to
the optimization of hyperthermic isolated limb perfusion, Eur. J.
Pharm. Sci. 5, 129-137 (1997).
- G. Bernhardt, I. Muckenschnabel, T. Spruss, A.
Buschauer preclinical tumorpharmacological and pharmacokinetic studies
on the adjuvant administration of hyaluronidase in the chemotherapy of
malignant melanoma. Naunyn-Schmiedeberg´s Arch. Pharmacol. 358 Suppl.2, 1: R 531 (1998)
- I.
Muckenschnabel, G. Bernhardt, T. Spruß, A. Buschauer,
Pharmacokinetics and tissue distribution of bovine testicular
hyaluronidase and vinblastine in mice: an attempt to optimize the
mode of adjuvant hyaluronidase administration in cancer chemotherapy,
Cancer Lett. 131, 71-84 (1998).
Related research topics: isolated limb perfusion, interstitial chemotherapy of brain tumours, Modulation of PGp (MDR-modulators), Hyaluronidases and inhibitors, Effect of hyaluronan and hyaluronidase on tumour growth and metastasis
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