Toycamycin Production Project For The National Cancer Institute

Toyocamycin (TM) is a pyrrolopyrimidine antibiotic which also serves as the precursor for chemical conversion to the antitumor agents sangivamycin and tricyclicnucleoside phosphate (TNP) (Fig. 1). These types of agents originally discovered as having antiviral activity were evaluated in phase II and phase III clinical trials against a variety of human cancers by the National Cancer Institute (NCI).

CEBTech has past experience with this Toyocamycin project involving the optimization of the shape of the total antibiotic productivity curve, QTM (g antibiotic/dm3 . total hours). The primary criteria in determining the success of manipulation of scale-up parameters such as oxygen transfer rate, impeller tip velocity and fluid mixing was whether the TM productivity was able to be increased or sustained longer at a higher level. This scale-up approach for a mycelial antibiotic fermentation differed from those previously reported. To evaluate QTM   on-line, a simple model was developed to predict antibiotic concentrations in ug/cm3  (titer) from the behavior of the oxygen uptake rate (OUR),   which could be continuously calculated from fermentor exhaust gas data. This predicted antibiotic titer could be compared with periodic high performance liquid chromatography (HPLC)   determinations of TM titer by fermentation operators to assess the reproducibility of QTM   behavior over time as the process was scaled from 120 dm3 to 1200 dm3 and eventually to 12,000 dm3.   Antibiotic productivity could be accurately predicted using oxygen uptake rate (OUR) without directly monitoring mycelial growth.

Oxygen uptake rates have previously been implicated as potentially useful for monitoring and control of nucleotide and nucleoside fermentation. This information along with previously reported fermentation conditions for production of TM and Sangivamycin from Streptomyces toycaenis and the effect of elevated incubation temperature on TM production by Streptomyces rimosus formed the basis for this medium optimization and scale-up approach (86, 288).


Plant Upper Level
Showing 120, 1200, &
12,000 dm3 Fermenters

Control Panels
for 120, 1200,
12,000 dm3 Fermenters

Toyocamycin
Structure and its
Derivatives

Changes
in Toyocamycin
Guanine & Adenine

Regulation of
Toyocamycin
Biosynthesis



General Run
Parameters for
TM Production


Effect of Impeller
Tip Velocity on
Toyocamycin Production


Effect of Programmed
Impeller Tip Velocity
on TM Production


Determination of OUR
and QTM Coefficients
from 120 dm3 Scale Data


Prediction of OUR
and QTM Values on Scale-up
to 12,000 dm3 Scale


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References