Phase I evaluation of low-dose suramin as chemosensitizer of doxorubicin in dogs with naturally occurring cancers.
BACKGROUND
Low and nontoxic concentrations (10-50 microM) of suramin, which is a nonspecific inhibitor of multiple growth factors, including fibroblast growth factors, enhances the activities of cytotoxic chemotherapeutic agents, such as doxorubicin and paclitaxel, both in vitro and in vivo. Suramin has not been evaluated as a chemosensitizing agent in dogs with cancer.


OBJECTIVE
Nontoxic suramin can be used safely as a chemosensitizer in dogs.


METHODS
Sixteen dogs of various breeds with measurable tumors were treated; 1 dog that had undergone amputation for osteosarcoma received adjuvant therapy.


METHODS
The dogs received 53 courses of treatment with suramin in combination with doxorubicin. The suramin dosage was 6.75 mg/kg IV 3 h before standard doxorubicin administration every 2 weeks. The pharmacokinetics and clinical efficacy were determined.


RESULTS
The pharmacokinetics of low-dose suramin followed a 2-compartment model with half-lives of 2 h and 6 days. The distribution volume was a 0.34 +/- 0.12 L/kg, and clearance was 1.86 +/- 0.76 mL/kg/h. During the time interval that doxorubicin was present at therapeutically active concentrations (ie, from the start of infusion to 24 hours), the plasma concentrations were maintained within 20% of the target range (8-60 microM) in 72% of the treatments. The toxicity of the suramin/doxorubicin combination was mild and comparable to the toxicity expected for doxorubicin monotherapy. Objective partial responses were observed in 2 out of 16 evaluable dogs (13%). All 5 dogs that previously received doxorubicin showed improved responses to the suramin/doxorubicin combination.


CONCLUSIONS
A fixed, low-dose suramin regimen yields the desired target plasma concentrations in most dogs, and appears to enhance the activity of doxorubicin without enhancing toxicity.
Kosarek
Carrie E
CE
College of Veterinary Medicine, The Ohio State University, Columbus 43210, USA.
Hu
Xiao
X
Couto
C Guillermo
CG
Kisseberth
William C
WC
Green
Eric M
EM
Au
Jessie L S
JL
Wientjes
M Guillaume
MG
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects; D004357:Drug Synergism; D005260:Female; D008297:Male; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000662:veterinary*; D009503:Neutropenia / Q000139:chemically induced / Q000662:veterinary; D010976:Platelet Count / Q000662:veterinary; D013498:Suramin / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics; D013921:Thrombocytopenia / Q000139:chemically induced / Q000662:veterinary
D013498:Suramin; D004317:Doxorubicin