Phase I and pharmacokinetic evaluation of intravenous hyaluronic acid in combination with doxorubicin or 5-fluorouracil.
BACKGROUND
Pre-clinically, hyaluronan (HA) has been demonstrated to systemically target chemotherapeutic drugs to tumours while ameliorating treatment toxicities. This study is a preliminary clinical investigation to determine if HA could be safely used in combination with 5-fluorouracil (5-FU) and doxorubicin (DOX).


METHODS
Thirty patients with metastatic cancer were intravenously administered 500 mg/m2 HA in combination with escalating doses of DOX (30-60 mg/m2) or 5-FU (cumulative dose of 1,350-2,250 mg/m2 per cycle). The effect of pre-administration of 20 mg/m2 of folinic acid on HA/5-FU chemotherapy was also investigated. Patients were randomized to receive either HA/chemotherapy or chemotherapy alone in their first treatment cycle and vice versa for the second cycle. Patients received HA and chemotherapy in all subsequent cycles.


RESULTS
Treatment was well tolerated, tumour responses were observed and the co-administration of HA did not alter the pharmacokinetics of clinically relevant doses of 5-FU or DOX.


CONCLUSIONS
High doses of intravenous high-molecular-weight HA can be safely co-administered with clinical doses of chemotherapy without significantly altering the toxicity or pharmacokinetics of the drugs or HA.
Rosenthal
Mark A
MA
Cancer Trials Australia, Department of Clinical Hematology, Medical Oncology and Palliative Care, Royal Melbourne Hospital, Melbourne, Australia.
Gibbs
Peter
P
Brown
Tracey J
TJ
Wong
Shirley
S
Uren
Shannon
S
Ellis
Andrew
A
Li
Lingli
L
Heldin
Paraskevi
P
Fox
Richard M
RM
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000276:Adjuvants, Immunologic; D000970:Antineoplastic Agents; D004317:Doxorubicin; D006820:Hyaluronic Acid; D002955:Leucovorin; D005472:Fluorouracil