Zurich, 14th May 2001
Decrease of CD-4 cells and CD-8 cells
and opportunistic infections effected by nucleoside analog drugs
Dear Sir or Madam
As you may learn from the enclosed
articles by Bruce Cheson and others, that summarise the experiences
made in the last 20 years with nucleosid analog substances in cancer
therapy, nucleoside analog substances cause a decrease of CD-4 cells
and CD-8 cells, a continuous impairment of the cellular immune
reactions (by the inhibition of the secretion of Interleucin 2 in Th-1
cells) and the occurence of lethal opportunistic infections (e.g. PCP,
cytomegalo-viruses, Herpes simples, Lysteriosa,
Non-A-non-B-hepatitis). As we have demonstrated earlier by various
studies, nucleoside analog substances, which have been used in cancer
therapy to effect programmed cell death, also cause damage to the
mitochondrial DNA and thereby severe damage to the brain, the muscles,
the bone marrow and to internal organs.
The occurence of this opportunisitc
infections and the decrease of CD-4 helpercells in a AIDS patients and
persons tested positive has not been traced back to a functional
suppression of cellular immune reactions as it comes about by frequent
infections (due to repeated injuries and dirty water), by repeated
contact of foreign proteins to the plasma (due to coagolation proteins
and unprotected anal intercourse), by hepatitis and the lack of
cysteine in nutrition, by antibiotics and nitrite drugs with high
oxydising effect and by nucleoside analog drugs (such as AZT) but not
to the HIV-viruses, which untill today could not be isolated or
demonstrated as transmittable, reproductible viruses according to the
established rules in virology.
The supporters of the antiviral AIDS
therapy in Europa and the USA now want to administrate the cocktail
therapy containing this nucleosid substances only to persons with full
blown AIDS and CD-4 cell counts below 100 (this after they had given
the guideline "hit the virus early and hard" in 1996). Now
they continue together with the producers to claim the broad
administration of this cytotoxic drugs in developing countries. They
do this after they have treated to death thousands of AIDS-patients
and persons tested positive (mainly male homosexuals, hemophiliacs and
druc addicts) in the last 15 years.
The action launched out in South Africa
against Glaxo Smith Kline, the producer of AZT, can bring new insights
in the immunotoxic and cytotoxic effects of AZT and other AIDS
medicaments, which are likely to the effects of nucleoside analog
substances demonstrated in the above mentioned articles.
Felix de Fries
Enclosure: - Bruce D. Cheson:
Toxicities associated with Purine Analog
Therapy: Summary
- Peng Huang: Induction of Apoptosis by Nucleoside Analogs: Summary
from Bruce D. Cheson, Michael J. Keating, William Plunkett
(Editors):Nucleoside Analogs in
Cancer Therapy, Marcel Dekker Inc. Basel, New York, Hongkong 1997
- Treatment recommendations
1) Toxicities Associated with Purine
Analog Therapy
Bruce D. Cheson
National Cancer Institute Bethesda, Maryland
V. Summary
The nucleoside analogs have proven to
be highly effective in the therapy of lymphoid malignancies. However,
they have a number of associated toxicities, some of what may be
severe. Of particular concern is immunosuppression wich is uniform
with standard treatment programs. Each of the nucleoside analogs is
associated with a profound lymphocytopenia, with a reversal of the
CD4/CD8, and opportunistic infections. Whether secondary malignancies
will be a long-range complication will require observation and
recording of long-term follow-up resulsts. The frequency with wich
many of the nonhematologic toxicities occur is difficult to estimate.
Most studies contain small numbers of patients, in whom few, if any
nonhematologic toxicities are reported. Whether that reflects the
actual rarity of these events or the care with which those series was
evaluated is not clear. As the clinical experience with these agents
become more extensive, with longer follow-up, recognized toxicities
will become better charatrized and new side effects ma be encountered.
Anecdotal reports may serve to increase the sensitivity for
identification of new and unusual complications. There are a number of
unresolved issues in the use of the nucleoside analogs. The optimal
schedule of administration remains unknown. A 6-month course of
fludarabine has been recommnded for CLL, and a similar duration of DCF
for HCL. Although a single course of CDA is generally used for HCL,
repeated courses have been delivered for the other lymphoid
malignancies. Nevertheless, these regiments are empiric. An
accumlating body of evidence suggests that fludarabine and CdA work by
a different mechnism of action, e.g., activation of apoptosis.
Therefore, we may be administering more drug than is required for
biological effect (199, 200). Further study of this issue is warranted
to maintain efficacy while minimizing the tocicities associated
with treatment with these highly effecive nucleosid analogs. As
nucleosid analogs are being combined with cytotoxic and biological
agents in an attempt to increase their efficacy, care must be
exercised to avoid drugs with overlapping toxicities.
Based on the published literature, the non-hematologic toxicities from
the nucleoside analogs are relatively similar (Table 3), with the
possible exception of the ocular toxicity, rash and increased severity
of nausea and vomiting with DCF, and the relatively more prolonged
period of immunosuppression with DCF and CdA. In general, however,
they are relatively well tolerated. The decision as to which is the
preferred nucleoside analog for a specific indication must be
determined by their response rate, durability of responses, cost,
toxicity profile and ease with wich they can be combined into
effective combination regiments.
2) Induction of Apoptosis by
Nucleoside Analogs
Peng Huang
The University of Texas, M.D. Anderson Cancer Center, Houston, Texas
Susan Wright
Mater Hospital, South Brisbane, Australia
V. Summary
Apoptosis is a key pathway by which
nucleoside analogs exert their cytotoxic action against cancer cells.
Although this class of drugs acts at multiple cellular targets, the
incorporation of the analogs into cellular DNA is a crtical event in
triggering apoptotic response. In proliferating cell population,
S-phase cells are most sensitive to apoptosis induction. Two distinct
size classes of DNA fragmentation, the internucleosomal and high
molecular weight DNA fragments, are associated with nuceloside
analog-induced apoptosis. The two types of DNA fragmentation are
distinguishable by their requirements for Ca2+ and responses to
phorbol ester treatment. High molecular weight DNA fragmentation is an
early event of DNA degradation that is critical for drug-induced
apoptosis, wheras activation a Ca2+-dependent endonuclease to cleave
DNA at internuclesomal sites is not an absolute requirement for the
execution of the apoptotic cell death program. Furthermore, high
molecular weight DNA fragmentation occurs in vivo and may be
correlated with the therapeutic activities of nucleoside analogs.
The factor responsable for high molecular weight DNA fragmentation is
a protein that requires MG2+, ATP, and neutral pH for optimal
activity. This activity is transferable by cell fusion and active in
isolated nuclei. Thus, the enzyme responsible for clevage of DNA int
HMW fragments may be considered as an execution molecule in the
apoptotic process. Figure 7 illustrates a proposed model of nucleoside
analog-induced apoptosis. During DNA replication, cells maintain a
normal level of DNA repair activity and keep the apoptotic program
inactive through the function of the proposed sensor molecule (e.g.,
DNA-PK/Ku). The incorporation of analogs into DNA terminates further
strand elongation, resulting in the generation of an abnormal DNA end.
A sensor molecule binds to the damaged DNA region and singals for
repair. If repair fails, the sensor molecule triggers the apoptotic
program by phosphorylating other proteins involved in the signaling
and execution of the cell death pathway. This apoptotic mechanism can
be regulated by a variety of regulatory molecules such as bcl-2,
bcr-abl, p53, and c-myc. A comprehensive understanding of the
mechanisms in drug induced apoptosis and ist regulation will provide a
base for developing more effective therapeutic strategies for cancer
treatment.
from: Nucleoside Analogs in Cancer
Therapy
edited by Bruce D. Cheson, Michael J. Keating, William Plunkett
Marcel Dekker Inc. New York, Basel, Hong Kong 1997
