Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
Creatine and Creatinine Metabolism - Physiological Reviews
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1156 MARKUS WYSS AND RIMA KADDURAH-DAOUK Volume 80<br />
siveness to cCr in a rat syngeneic model (641). Dietary<br />
cCr at 1% for 3–4 wk inhibited the growth of two rat<br />
mammary adenocarcinomas (Ac33tc <strong>and</strong> 13762A) as well<br />
as of MCI sarcoma by 20–50%. Cr at very high concentrations<br />
also inhibited the growth of some of the tumors,<br />
although in several other studies (60) (see also below), it<br />
was inactive.<br />
To optimize the therapeutic potency of cCr, different<br />
dosages, routes of administration, <strong>and</strong> schedules were<br />
compared in the rat mammary tumor 13762 (991). The<br />
antitumor activity was scored as difference in the number<br />
of days required for treated tumors to reach a volume of<br />
500 mm 3 as compared with untreated animals. Tumor<br />
growth delay was more pronounced at the higher cCr<br />
dosage (1.0 vs. 0.5 g � kg �1 � day �1 ) <strong>and</strong> when cCr was<br />
administered intravenously rather than intraperitoneally.<br />
The earlier the cCr administration was initiated, the better<br />
growth inhibition was noted. The tumor growth delay<br />
with cCr was comparable to that achieved with clinically<br />
used anticancer drugs such as the antitumor alkylating<br />
agents CDDP [cis-diamminedichloroplatinum(II) � cisplatin]<br />
<strong>and</strong> cyclophosphamide, the antitumor antibiotic<br />
adriamycin, or the antimetabolite 5-fluorouracil.<br />
Because cCr seems to be working through a unique<br />
mechanism of action, it might act synergistically with<br />
other agents. cCr was therefore tested both in vitro <strong>and</strong> in<br />
vivo in combination with several st<strong>and</strong>ard chemotherapeutic<br />
agents (991). The human small cell lung carcinoma<br />
cell line SW2 was only marginally responsive to cCr in<br />
vitro. When SW2 cells were incubated for 24 h with cCr<br />
<strong>and</strong>, additionally, during the fifth hour of cCr treatment<br />
with either one of four antitumor alkylating agents,<br />
CDDP, melphalan, 4-hydroperoxycyclophosphamide, or<br />
carmustine, a greater than additive killing of SW2 cells<br />
was observed (Fig. 14A). The antitumor alkylating agents<br />
used alone at the same concentrations were only moderately<br />
effective. In the rat mammary carcinoma 13762<br />
model in vivo, cCr given in combination with either<br />
CDDP, cyclophosphamide, adriamycin, or 5-fluorouracil<br />
resulted in longer tumor growth delays than those<br />
achieved with any of the anticancer drugs alone (Fig.<br />
14B). Favorably, no evidence of increased general toxicity<br />
was noted.<br />
The effect of combination therapies was also tested<br />
with cCr <strong>and</strong> adriamycin on the human prostate tumor<br />
cell line LNCaP both in vitro <strong>and</strong> in vivo (379). Survival<br />
curves determined in cell culture revealed that LNCaP<br />
cells are only moderately sensitive to adriamycin, with<br />
35% growth inhibition at a concentration of 8.4 �M. The<br />
combination of cCr <strong>and</strong> adriamycin produced additive to<br />
synergistic inhibition of cell proliferation, with the greatest<br />
effects being seen at the highest concentrations<br />
tested. For example, effects 10-fold greater than expected<br />
for additivity were observed for the combination of 6 mM<br />
cCr <strong>and</strong> 8.4 �M adriamycin. In vivo, cCr as a single agent<br />
FIG. 14. Synergistic antitumor activity of cCr in vitro (A) <strong>and</strong> in vivo<br />
(B). A: human SW2 small cell lung carcinoma cells were treated with<br />
either cyclophosphamide (4-HC) or cisplatin (CDDP) alone (F) orin<br />
combination with cCr (Œ). The shaded area represents the surviving<br />
fraction expected in case of an additivity of the antitumor effects. B:<br />
growth delay of rat 13762 mammary carcinoma produced by anticancer<br />
drugs in the presence or absence of cCr given intravenously. Tumor<br />
growth delay is defined as the difference in the number of days required<br />
for treated tumors to reach a volume of 500 mm 3 as compared with<br />
untreated controls. [Modified from Teicher et al. (991).]<br />
significantly inhibited the growth of LNCaP xenografts<br />
even when the tumor size was large. In contrast, adriamycin<br />
was not effective against larger tumors. Combined<br />
administration of cCr <strong>and</strong> adriamycin produced better<br />
tumor growth inhibition than either drug alone.<br />
To more clearly underst<strong>and</strong> the underlying basis of<br />
the cCr effects, the responsive ME-180 cervical carcinoma<br />
cell line was treated with a range of cCr concentrations,<br />
<strong>and</strong> the cell cycle distribution was examined after 0, 8, 16,<br />
<strong>and</strong> 24 h of drug treatment (602). FACS analysis revealed<br />
no major alterations in cell cycle distribution. A minor<br />
twofold accumulation in G 2-M was seen after 16 h but was<br />
not sustained. When synchronized ME-180 cells were analyzed,<br />
progression out of each phase (G 1,S,orM)was<br />
significantly reduced within the first 8hoftreatment with<br />
cCr. With continued treatment, progression was blocked.<br />
These results suggest that the predominant effect of the<br />
drug is to block progression out of all phases of the cell<br />
cycle.