A pilot dose-escalation study of the effects of nordihydroguareacetic acid on hormone and prostate specific antigen levels in patients with relapsed prostate cancer.
OBJECTIVE
To assess the tolerability of the effects of nordihydroguareacetic acid (NDGA) and its effect on prostate-specific antigen (PSA) kinetics in patients with relapsed prostate cancer, as among the many biological effects of NDGA is the inhibition of the insulin-like growth factor 1 receptor (IGF-1R) tyrosine kinase.


METHODS
Eligible patients were those with an increasing PSA level after definitive local therapy, in either the non-castrate (androgen-dependent prostate cancer, ADPC) or the castrate state (castration-resistant prostate cancer, CRPC) with no evidence of metastatic disease by bone scan or computed tomography of the abdomen or pelvis. Treatment consisted of continuous oral daily dosing according to a planned dose escalation of 750, 1250, 1750, 2250 and 2500 mg of NDGA. PSA levels were measured every 28 days. Serial levels of testosterone, dihydrotestosterone, oestradiol and sex hormone-binding globulin were measured at baseline and monthly while on study therapy.


RESULTS
Fifteen patients were enrolled, including 11 with ADPC and four with CRPC. There were asymptomatic increases in transaminase in six patients, two of which were grade 3, all occurring at >or=3 months. The increases in transaminase resolved after stopping NDGA but recurred with repeated dosing. Doses of NDGA up to 2500 mg/day caused no other toxicities. A median (range) of 5.5 (1-13) cycles were delivered. Of the 11 patients with ADPC, one had a decline in PSA level of >50% of the baseline value and one a decline of <50%. Three patients with ADPC had a greater than three-fold increase in PSA doubling time while on therapy, one from 11 to 46 months (750 mg), one from 9.5 to 49.5 months (1750 mg), and one from 5.9 to 46.2 months (2500 mg). There were no reductions in PSA level in patients with CRPC. There were no significant effects on levels of testosterone, dihydrotestosterone, oestradiol or sex hormone-binding globulin.


CONCLUSIONS
Continuous daily dosing with NDGA is reasonably well tolerated but is associated with transaminitis in some patients, that occurs after several months on therapy. There were apparent effects on the rate of increase in PSA. Further study is required to determine the optimum pharmacokinetics and antitumour effects of this therapy.
Ryan
Charles J
CJ
Department of Medicine and the [corrected] UCSF Comprehensive Cancer Center, University of California San Francisco, CA 94143, USA. ryanc@medicine.ucsf.edu
Harzstark
Andrea H
AH
Rosenberg
Jonathan
J
Lin
Amy
A
Claros
Christina
C
Goldfine
Ira D
ID
Kerner
John F
JF
Small
Eric J
EJ
Youngren
Jack F
JF
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D009637:Masoprocol / Q000627:therapeutic use*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D010865:Pilot Projects; D017430:Prostate-Specific Antigen / Q000187:drug effects*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017526:Receptor, IGF Type 1 / Q000187:drug effects; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D009637:Masoprocol; D017526:Receptor, IGF Type 1; D017430:Prostate-Specific Antigen