AIDS-Related
Lymphoma
By Mark Bowers
Lymphoma is a type of cancer in which the cells of the lymphoid tissue multiply
unchecked. Lymphomas are divided into 2 categories: Hodgkin's lymphoma, if a type of cells
called Reed-Steinberg cells are present, or non-Hodgkin's lymphoma (NHL). The rate of NHL
rose steadily among people with AIDS from 1989 to 1995. Research increasingly points to
cooperation between or among viruses to produce this kind of cancer. However, clinical
research on AIDS-related lymphoma in the brain is sadly lacking.
Incidence
Non-Hodgkin's lymphoma (previously called lymphosarcoma) is a type of cancer that
affects cells found mainly in the lymph nodes and the spleen. Leukemia and lymphoma are
the common names for cancer of the white blood cells. Cancer can transform any white blood
cell at any stage in the progression from bone marrow stem cells to mature T-cells and
B-cells. NHL can arise at any stage of HIV disease. The rate at which people with AIDS
develop NHL continued to rise until 1995, when highly active antiretroviral therapy (HAART
-- therapy combining more than one class of anti-HIV drugs) began to become widespread.
The increased number of people with HIV and NHL apparently was proportional to the extent
and duration of suppression of their immune systems.
Lymphoma affects HIV negative people at a yearly rate of 8 cases per 100,000 people.
About 54,000 cases will be diagnosed in the United States by the end of 1997. NHL ranks
sixth among cancers for the rate at which it affects new people and for the number of
people who die from it each year. Alan Aisenberg, MD, at Harvard Medical School estimates
that 24,000 people will die of NHL in 1997.
At the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in
Toronto, Patrick Yeni, MD, and colleagues from Hopital Pontchaillou in Rennes France,
presented data showing overall decreased rates of many opportunistic infections and
cancers among French patients taking HAART. NHL rates decreased since 1995, reversing a
6-year trend.
Between 1978 and 1990 there was a marked increase in HIV-associated NHL among gay men.
Aggressive B-cell NHL is an AIDS-defining diagnosis that now accounts for 2-3% of newly
diagnosed AIDS cases (called primary NHL), according to the Centers for Disease Control
and Prevention (CDC). This rate of NHL may be misleadingly low, since cases of NHL that
occur after another AIDS-defining infection (called secondary cases) are not reported to
the CDC. In 1994, the National Cancer Institute (NCI) estimated the probability of NHL
developing among people with AIDS at 19.4% by 36 months after starting antiretroviral
therapy. It is unclear how much that rate has decreased in the U.S. since the era of
HAART.
Increased rates of lymphoma have been associated with both sexual and intravenous
routes of exposure to HIV. A Pittsburgh, PA study of 33 HIV positive hemophiliacs with
AIDS-related NHL, of whom 21 had primary and 12 had secondary AIDS-related NHL, showed
that the HIV positive hemophiliac population had a 36-fold greater risk for NHL than HIV
negative hemophiliacs and a 29-fold greater risk than the general public. Survival after a
diagnosis of AIDS-related NHL was short, a median of 7 months for primary AIDS-related NHL
as compared with 2 months for secondary AIDS-related NHL. The proportion of secondary
cases is increasing, and is associated with prolonged immune suppression.
Causes of Lymphoma
Cancer is thought to be caused by genetic predisposition and environmental carcinogens
(cancer-causing agents). Lymphoma arises when a single lymphocyte (white blood cell)
accumulates a number of genetic mutations and loses control over its own reproduction.
This cell and its descendants continue to mutate and grow to form a tumor, often in
lymphatic tissue such as lymph nodes or the spleen. The greatest danger from lymphoma is
its spread to other organs and tissues of the body.
AIDS-related Kaposi's sarcoma (KS) has been clearly associated with dual infection with
HIV and the newly recognized Kaposi's sarcoma-associated herpesvirus (KSHV). Is there a
similar role for a virus in the development of lymphoma? Recent research supports an
active role for Epstein-Barr virus (EBV) in the development of lymphoma. One type of NHL,
Burkitt's lymphoma, has a proven association with EBV. Worldwide, EBV contributes to about
half of all cancers of the upper pharynx (throat), more than 30% of all cases of Hodgkin's
disease and 10% of NHL. The hypothesis that HIV enables other viruses to cause specific
cancers is worth further study. Research is needed to clarify the role of EBV in
AIDS-related lymphoma, while the relationship between KSHV and KS (see the March 1996
issue of BETA) and the role of human papillomavirus in anogenital cancer (see the September 1997 issue of BETA) are better understood.
Research is also needed to understand the relationship between newly found herpesviruses
and lymphoma. Such research could yield new ways to predict and treat lymphoma.
Biomonitoring is the direct measurement of toxins in people. The National Center for
Environmental Health (NCEH) is responsible for biomonitoring in the U.S. The NCEH
laboratory has collaborated during the last several years in a study with the NCI to
investigate possible links between NHL in HIV negative persons and exposure to
environmental toxins such as polychlorinated biphenyls (PCB) or pesticide exposure. In a
nested case-control study of 200 people, NCEH analyzed blood serum for PCB and pesticides.
Results showed a significant relationship between subjects' PCB serum level and their risk
for NHL. People who were most exposed to PCB were 4.5 times more likely to have NHL than
were people who were least exposed. NCEH also evaluated the presence of EBV antigen in
subjects' blood to assess the risk of developing NHL. People whose PCB levels were above
average and who also had the EBV antigen were 22.3 times more likely to have NHL than were
people whose PCB levels were below average and who did not have the EBV antigen. Because
of the small number of people in the study, further research needs to be done to confirm
the findings.
Occupational and environmental exposure, and the increase in cases because of the rise
in numbers of AIDS-related NHL cases, do not completely account for the 150% rise in NHL
cases since 1950. Better methods of detection and better reporting of cases may account
for some of the overall rise. However, it is irresponsible to draw hasty conclusions about
the underlying causes of AIDS-related lymphoma in the absence of a controlled study of
well-defined research questions. The cooperative role of HIV and other viruses in the
development of various types of cancer is clearly an area for increased research.
Symptoms and Signs
The warning signs for NHL include painless swelling in the lymph nodes in the neck or
groin, generalized itching, weight loss, fever and night sweats. HIV positive individuals
should beware of any swelling outside the lymph nodes. Medical examination of people with
NHL reveals an enlarged liver and spleen, while routine laboratory testing often reveals
anemia (low red blood cell count).
Diagnosis
The term non-Hodgkin's lymphoma refers to a collection of more than 24 kinds of cancer
of the lymphatic system. In order to offer appropriate treatment and to predict the
outcome, clinicians must first determine which lymphoid cells are affected by lymphoma. A
first step is to remove a sample of affected tissue for analysis (biopsy). Cells are
stained then viewed through a light microscope to compare sizes, cell shape and the
appearance of the cell nucleus and cytoplasm. The cells are classified as low grade
(slowly spreading), intermediate grade (more rapidly spreading) or high grade (very
aggressive). A comparison of symptoms with the results of computerized tomography (CT)
scans and magnetic resonance imaging (MRI) pictures completes the diagnosis.
NHL can affect many organs of the body. A person with HIV is more likely to have
lymphoma of more than one organ. A chest x-ray will reveal whether there is lung
involvement. A bone marrow biopsy helps determine whether the lymphoma has traveled to the
bone marrow, the site of production of all red and white blood cells. Again, a biopsy is
performed to remove some of the bone marrow, which is then viewed under a microscope for
cellular abnormalities. Finally, specialized x-rays can help visualize the structure of
swollen lymph nodes and examine the blood and lymph supply to them. This process, called
lymphangiography, requires the injection of blue dye into the web spaces between the toes
and then taking x-ray pictures of individual lymph nodes as the dye passes through them.
Treatment and Outlook
Two types of treatment are typically offered to people with NHL. Chemotherapy consists
of drugs that seek and destroy cancer cells. Targeted radiation therapy uses modified
x-rays to kill cancer cells and shrink tumors. A combination of radiation and chemotherapy
is usually chosen and tailored to fit individual needs and circumstances.
There is controversy about the best chemotherapy for AIDS-related NHL. A regimen called
CHOP, consisting of cyclophosphamide, doxorubicin, vincristine and prednisone, has been
proposed for treating AIDS-related lymphoma because it is regarded as standard for people
without HIV infection. Proponents of this combination recognize that individualized
choices must be made both about the drugs that will be used and the amount by which the
doses will be reduced, based on immune status and the individual's ability to tolerate
very toxic treatment. All participants in the debate about which chemotherapy combination
to choose acknowledge that effective antiretroviral therapy may have an important effect
on overall survival.
Chemotherapy and radiation both destroy large numbers of immune system cells.
Neutropenia (a decrease in neutrophils, a type of white blood cell) can be prevented
before chemotherapy or radiation by the use of granulocyte colony stimulating factor.
After chemotherapy and radiation, autologous (self-donated before treatment) bone marrow
transplantation often is needed to bring back the immune system. Bone marrow transplants
are more commonly done in HIV-negative people, among whom 75% with low-grade localized NHL
live at least 5 years; 40-50% of those with more severe cases live 2 or more years.
Palliation - Care When There is No Cure
Treatments for NHL profoundly suppress the immune system. After chemotherapy and
radiation, frequently there is a need for glucocorticoids, anti-seizure medications and
pain control with strong pain killers. Adequate control of swelling and pain is usually
possible, and addiction is rarely a credible risk. When lymphoma cannot be controlled by
chemotherapy and radiation, comfort is a primary concern of the patient, physician, family
and friends.
NHL of the Brain - A Special Case
Lymphoma of the brain is rare in individuals with high CD4 cell counts. Recent reports
from ICAAC suggested that the rate of new cases of NHL of the central nervous system (CNS)
is decreasing among people who use HAART, reversing a previous trend.
The symptoms of primary CNS lymphoma are headache and fever. A feeling of increased
pressure in the head or even seizures are also common. Up to one-third of people with CNS
lymphoma experience problems producing speech (aphasia), visual field loss and sensitivity
or coordination problems on one side of the body.
According to the Mayo Clinic, early warning signs of CNS lymphoma can be detected in
the eye. In 11% of people who were later found to have CNS lymphoma, uveitis (inflammation
of the iris and surrounding parts of the front of the eye) preceded other symptoms by
months to years. If corticosteroid therapy does not correct uveitis, a biopsy of the
vitreous fluid in the eye that shows dense infiltration (inflammatory cells and debris)
can establish CNS lymphoma early, when the chances of benefiting from treatment are
greatest. Regular eye check-ups could help detect CNS lymphoma more often than is now
typical, and are far less frightening than a brain biopsy.
A physician who suspects NHL in the central nervous system will review the results of
MRI or CT for lesions in the brain. A brain biopsy is then needed to confirm the
diagnosis. An alternative method of detection that does not require biopsy is single
photon emission spectography (SPECT), a technique that measures tiny amounts of
radioactive substances called radionuclides that are injected and taken up by different
tissues in the body at different rates. A 1995 study by MA Pierce, MD, and colleagues from
Vanderbilt University used this technique to correctly identify 7 of 7 toxoplasmosis brain
lesions and 6 of 6 lymphoma lesions (see the December 1996 issue of BETA, page 50).
Often there are several lesions deep in the brain tissue with evidence of swelling
(edema) around each one. If these signs are present, Lisa De Angelis, MD, at Memorial
Sloane Kettering Cancer Center argues that the corticosteroids usually used to control
swelling should not be started immediately unless they are urgently required, since they
will make it more difficult to confirm the diagnosis. Corticosteroids can shrink affected
tissues so much that surgeons are then unable to locate affected tissue for a biopsy.
Primary CNS lymphoma is regularly underdiagnosed. Half of all cases are found only at
autopsy. Because the initial radiographic findings are similar, often patients are started
on antibiotics for toxoplasmosis, whether or not antibodies to the disease-causing
organism Toxoplasma gondii are found in the blood or in the cerebrospinal fluid around the
brain and spinal cord. Antibiotics may cause further deterioration in people with CNS
lymphoma and delay accurate diagnosis.
At the Infectious Diseases Society of America 35th Annual Meeting, held in September
1997 in San Francisco, C. Nelson, MD and colleagues at the University of Pennsylvania
reported the outcomes of patients with AIDS and CNS mass lesions. Of 45 people with
lesions, 35 were presumed to have toxoplasmosis and were put on antibiotic therapy. Of
these 35, only 14 were later proven to have toxoplasmosis infection (2 of these people
also had lymphoma). The cause of the brain lesions was determined in 13 people to be
lymphoma, in 2 to be progressive multifocal leukoencephalopathy, in 2 to be tertiary
syphilis, in 1 to be vasculitis, and the other 2 were lost to follow-up. The researchers
concluded that empirical anti-toxoplasmosis therapy for CNS mass lesions may not always be
warranted.
Alexandra Levin, MD, and colleagues from the University of Southern California,
reported at the XI International Conference on AIDS in Vancouver that mitoguazone
dihydrochloride plus standard doses of radiation benefited some people with AIDS-related
lymphoma in the brain. Survival times were increased from an average of 2 to as long as 11
months.
Several sources suggest the use of radiation therapy for NHL in the brain, and the
procedure has become an informal standard of care. A recent New England Journal of
Medicine article by Lawrence Kaplan, MD, suggested that decreased radiation and lowered
doses of chemotherapy may be as effective as standard doses, with fewer harsh side effects
when treating individuals with higher CD4 cell counts (Kaplan's standard chemotherapy,
called m-BACOD, consists of methotrexate, bleomycin, doxorubicin, cyclophosphamide,
vincristine and dexamethasone). Furthermore, chemotherapy decreases total white blood
counts, worsening immune suppression in people in whom this is already a significant
challenge.
Because people with AIDS-related lymphoma of the brain do not survive long (on average
2-5 months) after conventional combinations of radiation and corticosteroids, several
physicians have added chemotherapy including methotrexate, thiotepa and procarbazine to
the standard course of radiation. A comparison of 10 individuals treated with this
combination suggested that a few patients may benefit, with survival extended to longer
than a year (2 of Kaplan's patients lived more than 12 months). Parkash Gill, MD, and
others at the University of Southern California reported 1 patient who survived more than
28 months and another who survived more than 16 months.
Primary central nervous system lymphoma is very aggressive and does not respond well to
any treatments yet found. About 75% of cases at first respond to radiation therapy, but
most often there is soon a recurrence of NHL. Physicians attempt to eliminate or shrink
the tumor until their efforts are seen to fail.
Clinical Studies
Earlier in the HIV epidemic, research on NHL anywhere in the body was widely considered
a waste of valuable resources. This attitude was proven wrong, and survival rates for
people with NHL have improved. More than half of all people with NHL survive more than 5
years after detection and treatment. This survival rate is based on comparison with a
similar group of people without cancer. Research designed to improve the success and
safety of bone marrow transplants, frequently used to strengthen the decimated
blood-making system of patients after chemotherapy or radiation therapy, is expected to
improve these survival rates.
Researchers are now also trying to understand why viruses cause cancer in some people,
but not in others. HIV or immune suppression may trigger secondary factors or events in
the body that allow a normally uneventful EBV infection to produce lymphoma. Despite the
number of people who are affected by primary NHL of the brain, the disease process has
been very difficult to study. The AIDS Clinical Trials Group Oncology Committee designed a
study of this kind of lymphoma, but discontinued it after only 4 people entered the
protocol. The Division of AIDS believes that neurosurgeons will not perform biopsies on
people suspected of primary CNS lymphoma because of fear of contagion of HIV to themselves
or to their operating room teams. The committee further believes that primary care
physicians generally will not refer patients with suspected CNS lymphoma to specialists,
and that specialists will not treat them because of their conviction that the disease is
rapidly aggressive and incurable. Such attitudes were common at the outset of the AIDS
epidemic, but research has proven that up to one-half of all people with previously
untreatable systemic lymphoma achieved complete remission after low-dose chemotherapy.
The complete absence of a study population with CNS lymphoma makes it nearly impossible
for researchers to learn more about the disease or to find useful treatments.
Unfortunately, given current attitudes, the responsibility now falls on patients and their
primary care physicians to advocate forcefully and continuously for a proper diagnosis
including biopsy, to persuade radiation and oncology physicians to treat CNS lymphoma, and
to experiment with low-toxicity chemotherapy and low-level radiation to achieve the best
results. Early detection by non-invasive tests such as eye examinations for uveitis and
SPECT scans should also be advocated.
The greatest gap in NHL research is antiviral research. The obvious target is
Epstein-Barr virus, so clearly connected with various cancers that affect millions of
people worldwide. A retrospective case control study of 29 patients at the University of
Toronto suggested that long-term, high-dose acyclovir (Zovirax) may help prevent NHL (see
the March 1997 issue of BETA, page 46). This small study showed a possible relationship
between reducing EBV and controlling EBV-associated cancers, but no concerted effort is
yet underway to develop antiviral drugs specifically targeting EBV.
Lobucavir, a drug originally developed as an anti-HIV therapy, has shown some activity
against EBV, but research has been stalled. Test tube studies revealed that lobucavir is
active against many herpesviruses, including cytomegalovirus (a cause of retinitis), EBV,
varicella zoster virus (the cause of shingles) and both herpes simplex type 1 and type 2
viruses (the cause of cold sores and genital herpes). Further study of lobucavir, perhaps
combined with acyclovir, may find an effective preventive regimen for NHL. Given the low
cure rate for AIDS-related NHL, prevention is the greatest hope.
Mark Bowers is Managing Editor of treatment publications at the San Francisco AIDS
Foundation.
Selected NHL Studies
The Trials Search Guide to HIV Clinical Trials in California lists 11 studies that are
evaluating various treatments for non-Hodgkin's lymphoma (NHL) in people with HIV. All of
these studies exclude people with lymphoma of the brain. More information about
participating in listed studies can be found in the Trials Search Guide, available by
calling 800-492-5777, or on the internet at http://hivinsite.ucsf.edu/tsearch.
Chemotherapy studies
Gallium nitrate, by injection into a vein (infusion) every day for 7
days, repeated every 3 weeks. The study lasts indefinitely. Participants must have tried
at least one other therapy and will have a spinal tap.
Cyclophosphamide, mitoxantrone and etoposide, by infusion into a
surgically-implanted catheter in the chest every 3-4 weeks. The study lasts 4-6 months.
Mitoguazone, cyclophosphamide, adriamycin, vincristine and prednisone,
by infusion in a 4-6 month study. Requires CAT scan of the head and a spinal tap.
PEG L-asparaginase, an early safety study of a new chemotherapy given
by injection into the muscle tissue. This study is for people who relapse or do not
respond to other methods to treat NHL. Each new patient receives a slightly higher dose of
drug to determine the largest dose that can safely be given. Requires spinal tap, CAT scan
of the head and bone marrow biopsy.
DaunoXome, given by infusion to people who do not respond to at least
one other chemotherapy. Requires bone marrow biopsy.
5-Azacytidine for EBV-related cancer, given by 7-day continuous
infusion to people who relapse or do not respond to other chemotherapy. The drug is
thought to have a direct effect on EBV.
Topotecan, given by 30-minute infusion on 5 consecutive days every 21
days. Must have received at least 1 but no more than 2 prior treatments with chemotherapy.
Everyone must go through at least two 21-day cycles.
Diethylhomospermine (DEHSPM), a dose-escalating study in which the
first group of participants receives the lowest dose. If no bad side effects are observed,
the next group of participants will receive a higher dose. DEHSPM is given by injection
under the skin every day for 6 days, and this cycle is repeated every 3 weeks.
Immune-based therapy studies
90Y-Lym-I, an immunotherapy given by infusion every 4 weeks for 12
weeks. Participants may continue to participate until they no longer respond to the
therapy. Participants will receive combination therapy with d4T, 3TC and indinavir to see
if the addition of HAART to standard cancer chemotherapy has an effect on treating
lymphoma. The study lasts 1 year.
Interleukin 2 (IL-2), an immune modulator given at home by injection
under the skin by study participants themselves. The study lasts one year.
References
Aisenberg AC. Understanding non-Hodgkin's lymphoma.
Science and Medicine 4:28-37. May/June 1997.
Antinori A and others. Diagnosis of
AIDS-related focal brain lesions: a decision-making analysis
based on clinical and neuroradiologic characteristics combined
with polymerase chain reaction assays in CSF. Neurology
48:687-694. 1997.
Bashir R and others. T-cell infiltration
of primary CNS lymphoma. Neurology 46:440-444. 1996.
Bashir R and others. Expression of
Epstein-Barr virus proteins in primary CNS lymphoma in AIDS
patients. Neurology 43:2358-2362. 1993.
Bignon YJ and others. Detection of
Epstein-Barr virus sequences in primary brain lymphoma without
immunodeficiency. Neurology 41:1152-11553. 1991.
Bonini C and others. HSV-TK gene transfer
into donor lymphocytes for control of allogeneic graft-versus-leukemia.
Science 276:1719-1724. June 13, 1997.
Cohen J. Epstein-Barr virus and the
immune system. Journal of the American Medical Association
278:510-5513. August 1997.
DeAngelis LM. Primary central nervous
system lymphoma. Neurology 41:619-621. 1991.
DeLuca A and others. Evaluation of
cerebrospinal fluid EBV-DNA and IL-10 as markers of in vivo
diagnosis of AIDS-related primary central nervous system
lymphoma. British Journal of
Haematology 90(4):844-849. August
1995.
Dent A and others. Control of inflammation,
cytokine expression, and germinal center formation by BCL-6.
Science 276:589-592. April 25, 1997.
Forsyth P and others. Combined-modality
therapy in the treatment of primary central nervous system
lymphoma in AIDS. Neurology 44:1473-1479. 1994.
Galetto G and others. AIDS-associated
primary central nervous system lymphoma. Journal of the
American Medical Association 26992-93. January 1993.
Hochberg FH and others. Central nervous
system lymphoma related to Epstein-Barr virus. New England
Journal of Medicine 309:745-748. September 1983.
Hodge M and others. NF-AT-drive interleukin-4
transcription potentiated by NIP45. Science 274:1903-1905.
December 13, 1996.
Komanduri K and others. The natural
history and molecular heterogeneity of HIV-associated primary
malignant lymphomatous effusions. Journal of Acquired
Immune Deficiency Syndromes and Human Retrovirology 13:215-226.
1996.
Lachance DH and others. Cyclophosphamide,
doxorubicin, vincristine and prednisone for primary central
nervous system lymphoma: short-duration response and multifocal
intracerebral recurrence preceding radiotherapy. Neurology
44:1721-1727. 1994.
Levin A and others. Mitoguazone with
radiation therapy in AIDS-related primary CNS lymphoma.
XI International Conference on AIDS, Vancouver, BC. July
7-12,1996. Abstract Th.B.184.
Michellet C and others. Opportunistic
infection occurred under protease inhibitors in HIV patients.
37th Interscience Conference on Antimicrobial Agents and
Chemotherapy, Toronto, September 28-October 1, 1997. Abstract
I-29.
Moghaddam A and others. An animal model
for acute and persistent Epstein-Barr virus infection. Science
276:2030-2033. June 27, 1997.
Morgello S and others. HHV-8 and IADS-related
CNS lymphoma. Neurology 48:1333-1335. 1997.
Moyle G. Occurrence of lymphomas during
ddC or ddC/zidovudine combination therapy in persons infected
with HIV type 1. Journal of Acquired Immune Dieficiency
Syndromes and Human Retrovirology 13:464-465. 1996.
Nelson C and others. Outcomes of patients
with AIDS and CNS mass lesions. Infectious Diseases Society
of America 35th Annual Meeting, San Francisco. September
13-16, 1997. Abstract Poster 551.
O'Neill B and others. Primary central
nervous system lymphoma. Mayo Clinic Proceedings
64:1005-1020. 1989.
Paulus W and others. Human herpesvirus-6
and Epstein-Barr virus genome in primary cerebral lymphomas.
Neurology 43:1591-1593. 1993.
Pialoux G and others. Central nervous
system as a sanctuary for HIV-1 infection despite treatment
with zidovudine, lamivudine and indinavir. AIDS 11:1302-1303.
1997.
Pluda JM and others. Development of
non-Hodgkin's lymphoma in a cohort of patients with severe
human immunodeficiency virus (HIV) infection on long-term
antiretroviral therapy. Annals of Internal Medicine 113:276-282.
1990.
Ragni M and others. AIDS-associated
non-Hodgkin's lymphomas as primary and secondary AIDS diagnoses
in hemophiliacs. Journal of Acquired Immune Deficiency
Syndromes and Human
Retrovirology 13:78-86. 1996.
Schwartz R. Hodgkin's disease - time
for a change. New England Journal of Medicine 337:495-496.
August 14, 1997.
Tirelli U and others. HCV and HIV-related
non-Hodgkin's lymphoma. Journal of Acquired Immune Deficiency
Syndromes and Human Retrovirology 14:80. 1997.
Uckun F and others. BTK as a mediator
of radiation-induced apoptosis in DT-40 lymphoma cells.
Science 273:1096-1100. August 23, 1996.
Page last updated 05 February 1998
|
