Animal Models
Animal Models of Cancer
Zadaxin has been shown to have beneficial effects in
several experimental models of cancer. Recently, Zadaxin treatment
has been shown to prevent lung carcinogenesis in mice injected
with a chemical carcinogen (52-54) and breast cancer in rats.
(55)
| Zadaxin, given
in combination with chemotherapy and IL-2 or interferon: |
| • |
Increased
the cytotoxic response of T cells and NK-cell activity |
| • |
Reduced tumor
size |
| • |
Increased
survival in many animal models of cancer |
| |
| – |
DHD/K12 colon carcinoma
(72,77) |
| – |
B-16 melanoma (29,78) |
| – |
Non–small-cell
lung cancer (53) |
| – |
Lewis lung carcinoma
(73,98) |
| – |
Friend erythroleukemia
(74) |
| – |
P388 or L1210 leukemia
(75) |
| – |
Methylcholanthrene-induced
fibrosarcoma (76) |
|
| Zadaxin treatment
shows synergy with IL-2 or IFNα/β: |
| • |
Syngeneic BDIX rats with
liver metastases from colorectal cancers induced by splenic
injection of DHD/K12 cells (1,2-dimethylhydrazine-induced
colon carcinoma) (72) |
| |
| – |
Greatly reduced growth
of liver metastases |
| – |
Reduced liver invasion
(20% vs 62% in controls) |
| – |
Reduced extrahepatic
spread |
| – |
Improved median survival
time (70.0 ± 8.2 days vs 48.5 ± 8.5
days in controls) |
| – |
Effect not seen with
5-FU alone or in combination with IL-2 |
| – |
P < 0.000 |
|
| The improvement
of survival time in these rats from the use of triple
combination therapy allowed for a second cycle of treatment
to be provided. (77) This
led to: |
| • |
Further significant increase
in survival time (81% survival at 100 days versus 39%
with 5-FU alone or 44% with 5-FU plus IL-2) |
| • |
Long-term survival in
2 of the 21 rats treated for two cycles of triple therapy |
| |
| – |
No evidence of disease
when sacrificed 5 months after therapy for histologic
evaluation |
|
| • |
Significant improvements
to parameters of the immune system — compared with
controls, increased absolute numbers of peripheral T cells
expressing |
| |
| – |
IL-2 receptors |
| – |
CD4 |
| – |
CD8 |
|
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More recent studies with a mouse model of melanoma showed that
combination of increasing doses of Zadaxin with IFNα/β
and chemotherapy significantly increased time to relapse (Figure
5), decreased the tumor growth rate (Figure
6), and improved survival in a dosedependent fashion. (78)
Significantly, the addition of a single cycle of Zadaxin treatment
led to a cure in 24% of the mice (5 of 21 animals were alive
and disease free 1 year after treatment). As in other studies
investigating the effects of Zadaxin treatment in animal models
of cancer, immune parameters were improved. Splenocytes from
treated mice showed markedly increased cytotoxic activities
against both YAC-1 and autologous B16 tumor cells, and the tumor-induced
reduction in percentages of CD3 and CD4 cells was reversed to
nontumor levels. (78)
| Figure 5. Relapse time
of B16 melanoma bearing mice treated with CY, IFN, and
ZDX. The figure shows that ZDX increases relapse time
of mice with B16 melanoma. Increasing doses of ZDX (up
to 120 µg) show the greatest effect on relapse in
this model. (78) |
Values are mean ± S.D.; n = 10
* CY = cyclophosphamide
** Equivalent to human dose |
| Figure 6. Effect of increasing
doses of Zadaxin on tumor reduction in murine B16 melanoma.
The figure shows that Zadaxin decreases tumor diameter
in mice with B16 melanoma. Increasing doses of Zadaxin
(up to 120 µg) increases the effect on tumor shrinkage
in this model. (78) |
* CY = cyclophosphamide
** Equivalent to human dose |
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