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cyclooxygenase pathway 205 cyclosporine (cyclosporin A; ciclosporin)
of human neoplasms. Cyclins are proteins that govern
transitions through distinct phases of the cell cycle by
regulating the activity of the cyclin-dependent kinases. In
mid to late G1, cyclin D1 shows a maximum expression
following growth factor stimulation. It has been successfully
employed and is a promising tool for further studies in
both cell cycle biology and cancer associated abnormalities.
This antibody is useful for separating mantle cell lymphomas
(cyclin D1-positive) from SLLs and small cleaved cell
lymphomas (cyclin D1-negative).
cyclooxygenase pathway
The method whereby prostaglandins are produced by enzymatic
metabolism of arachidonic acid derived from cell membranes,
as in type I (anaphylactic) hypersensitivity reactions.
cyclophilins
Cytoplasmic proteins that combine with immunosuppressive
therapeutic agents cyclosporin A and tacrolimus. T cell
activation is inhibited by the binding of calcineurin by the
drug–cyclophilin complex. An 18-kDa protein in the cytoplasm
that has peptidyl– prolyl isomerase functions. It has a
unique and conserved amino acid sequence that has a broad
phylogenetic distribution. It represents a protein kinase with
a postulated critical role in cellular activation. It serves as
a catalyst in cis-trans-rotamer interconversion. It catalyzes
phosphorylation of a substrate that then serves as a cytoplasmic
messenger associated with gene activation. Genes
coding for the synthesis of lymphokines would be activated
in helper T lymphocyte responsiveness. Cyclophilin has
a high affinity for cyclosporine (CSA), which accounts
for the immunosuppressive action of the drug. Inhibition
of cyclophilin-mediated activities as a consequence of
CSA–cyclophilin interaction may lead to inhibition of the
synthesis and release of lymphokines. CSA not only inhibits
primary immunization, but it may also halt an ongoing
immune response. This has been postulated to occur through
inhibition of continued lymphokine release and by suppression
of continued effector cell activation and recruitment.
2
5
Cyclophilin
11
CsA
Cyclosporine (CSA) bound to cyclophilin.
cyclophosphamide
(N,N-bis-[2-chloroethyl]-tetrahydro-2H-1,3,2oxazaphosphorine-2-amine-2-oxide),
a powerful immunosuppressive
drug that is more toxic for B than for T lymphocytes;
therefore, it is a more effective suppressor of humoral
antibody synthesis than of cell-mediated immune reactions.
It is administered orally or intravenously and mediates its
9
Nuclear magnetic resonance (NMR) structure of cyclosporine A as bound to
cyclophilin A.
H 2 C
H 2 C
H 2 C
NH
CH 2 CH 2 Cl
CH 2 CH 2 Cl
cytotoxic activity by crosslinking DNA strands. This alkylating
action mediates target cell death. It produces dose-related
lymphopenia and inhibits lymphocyte proliferation in vitro.
It destroys proliferating lymphoid cells and may alkylate
some resting cells. The greater effect on B than on T cells
is apparently related to the lower rate of recovery of B cells.
Very large doses of >120mg/kg intravenously over several
days may facilitate induction of specific tolerance to a foreign
antigen if the drug is administered simultaneously with or
immediately following the antigen. Cyclophosphamide is
beneficial for the therapy of various autoimmune disorders,
including rheumatoid arthritis, systemic lupus erythematosus
(SLE)-associated renal disease, Wegener’s granulomatosis
and other vasculitides, and autoimmune hematologic
disorders, including idiopathic thrombocytopenic purpura,
pure red cell aplasia, and autoimmune hemolytic anemia.
Cyclophosphamide is also used to treat Goodpasture’s syndrome
and various glomerulonephritides. Its beneficial use as
an immunosuppressive agent is tempered by the finding of its
significant toxicity, such as its association with hemorrhagic
cystitis, suppression of hematopoiesis, gastrointestinal symptoms,
etc. It may also increase the chance of opportunistic
infections and be associated with an increased incidence
of malignancies such as non-Hodgkin lymphoma, bladder
carcinoma, and acute myelogenous leukemia.
cyclosporine (cyclosporin A; ciclosporin)
A cyclic endecapeptide of 11 amino acid residues isolated
from soil fungi that has revolutionized organ transplantation.
O
P
O
N
Structure of cyclosphosphamide.
C