124
further explored in randomized trials. At present, however, the
data on the activity of anthracyclines and ifosfamide is more
solid, and determination of the best schedule for combining
the two agents should probably have priority.
In the editorial accompanying our paper Dr. Verweij indicated that the use of GM-CSF could have influenced the
therapeutic activity seen [8]. This contention is based on the
data of Edmondson et al. [9,10] that suggested that the efficacy
of a combination of IFOS, doxorubicin, mitomycin-C and
cisplatin could be improved by systematic administration of
molgramostin (GM-CSF), the product we used in our trial, at
5 ug/kg every 12 hours. In that pilot study all patients received
GM-CSF during 14 days after the combination was given, and
nine patients also received this agent prior to chemotherapy,
from day - 6 to day - 3 . One partial and four complete remissions were observed in 11 patients with STS, with three of the
responders progressing within the year, and all responsive
types corresponding to histologic subtypes sensitive to IFOS
and doxorubicin. This data from a small number of patients is
not especially remarkable and can be attributed to hazard
rather than to a GM-CSF effect. In our study there was a
similar response rate either before or after patients received
GM-CSF, although administration criteria and dosing were
completely different from those utilized by the Mayo Clinic
investigators. Objective remissions were observed in 11 of 23
patients who never received or before receiving GM-CSF, and
in six of 22 patients who responded while receiving GM-CSF
(x , P = 0.155, two-tailed). In our opinion, there is no consistent data to support or preclude the use of a specific type of
CSF in patients with STS nor to justify a randomized study.
There are many biological aspects of STS still unknown
that may explain the discordant results reported by different
authors. We agree with Dr. Verweij that perhaps it is no longer
adequate to treat so many different histological types (diseases?)
in the same way. This could only be possible by combination of
the efforts of the different groups studying these relatively
uncommon tumors.
J. M. Buesa on behalf of the Spanish Group for Research
on Sarcomas (GEIS)
Servicio de Oncologia Medica, Hospital Central de
Asturias, Oviedo, Spain
References
1. Verweij J. Etoposide for soft tissue sarcomas: Fact or fiction. Eur
J Cancer 1997; 33: 1527-8 (Editorial).
2. Saeter G, Alvegard TA, Monge OR et al. Ifosfamide and continuous infusion etoposide in advanced adult soft tissue sarcoma. A
Scandinavian Sarcoma Group phase II study. Eur J Cancer 1997;
33:1551-8.
3. Saeter G, Talle K, Solheim O. Treatment of advanced, high-grade
soft-tissue sarcoma with ifosfamide and continous-infusion etoposide. Cancer Chemother Pharmacol 1995; 36:172-5.
4. Yalcin S, Gullu I, Bansta I et al. Treatment of advanced refractory
sarcomas with ifosfamide and etoposide combination chemotherapy. Cancer Invest 1998; 16: 297-302.
5. Crawley ChR, Judson IR, Verrill M et al. A phase I-II study of a
72-hour continuous infusion of etoposide in advanced soft tissue
sarcoma. Sarcoma 1997; 1: 149-54.
6. Bramwell VHC, Mouridsen HT, Santoro A et al. Cyclophosphamide versus ifosfamide: Final report of a randomized phase II
trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol 1987;
23:311-21.
7. Antman K.H, Ryan L, Elias A et al. Response to ifosfamide and
mesna: One hundred twenty-four previously treated patients with
metastatic or unresectable sarcoma. J Clin Oncol 1989; 7:126-31.
8. Verweij J. High-dose ifosfamide for soft tissue sarcomas: Set the
scene, or senescence? Ann Oncol 1998; 9: 807-9 (Editorial).
9. Edmonson JH, Long H, Kvols LK. Cytotoxic drugs plus subcutaneous granulocyte-macrophage colony-stimulatig factor: Can
molgramostim enhance antisarcoma therapy? J Natl Cancer Inst
1994; 86: 312-3 (Letter).
10. Edmonson JH, Long HJ, Kvols LK et al. Can molgramostim
enhance the antitumor effects of cytotoxic drugs in patients wiht
advanced sarcomas? Ann Oncol 1997; 8: 637-41.
Oral ipriflavone (7-isopropoxyisoflavone) treatment for elderly
patients with resistant acute
leukemias
It has been reported that the flavonoid, quercetin (3,3',4',5,7pentahydroxy-flavone), inhibits cell growth in several cancer
cell lines and is capable of increasing the antiproliferative
activity of cytotoxic agents [1-2]; quercetin is able to inhibit
leukemic cell proliferation and colony formation by acute
myeloid and lymphoid leukemic progenitors without suppressing normal myelopoiesis [3, 4]. Moreover, we have shown
that quercetin has a pronounced synergistic antiproliferative
effect with cytarabine (ara-C) on both HL-60 cell line proliferation and the clonogenic capacity of primary human leukemic
cells [5].
Eleven patients with acute leukemias, nine of them with
acute myeloid leukemia (AML) and two with acute lymphoid
leukemia (ALL; median age 70, range 53-76), were treated
with ipriflavone. Seven of the 11 were resistant to conventional
chemotherapy; 3 were in first relapse and 1 was in second
relapse.
Ipriflavone was started as second-line treatment after the
failure of conventional cytotoxic treatment in patients in poor
clinical condition. In fact, five patients presented cardiovascular
disease that had worsened following antineoplastic treatments,
and four presented diabetes requiring insulin treatment.
A three-time daily dose of oral ipriflavone 600 or 400 mg
was administered alone in four patients, in combination with
hydroxyurea (1 g/day) in four cases, with oncovin (2 mg/week)
in two cases and ara-C (15 mg/twice daily for 15 days monthly)
in one patient.
After two months of treatment, three patients (two AML
and one ALL) had achieved partial remissions lasting 11,7, and
10 weeks. One patient was treated with ipriflavone alone, one
concomitantly with hydroxyurea and one with oncovin.
Seven of 11 thrombocytopenic patients (median platelet
count before starting ipriflavone treatment 20 * 109/l, range
10-35) showed increases in platelet count with a consequent
reduction in supportive treatment (median platelet count 35 x
109/l, range 30-55). Eight patients presented marked reductions of mucocutaneous hemorrhages. We observed no severe
side effects of ipriflavone aside from moderate nausea and
vomiting in three patients and mild liver toxicity in one. The
compliance of ipriflavone (6-12 capsules/day) was good.
Preliminary data presented in this study show that treatment with ipriflavone, alone or in association with other antineoplastic agents, is well tolerated with good compliance and
without hematological or extra-hematological side effects. In
125
three patients ipriflavone induced partial remission, and
although the median survival of our patients after the onset of
ipriflavone treatment was only 30 weeks, the supportive care
requirements were markedly reduced together with hemorrhagic manifestations. This therapeutic effect may be due to both
the increase in platelet counts and the protection of vascular
wall demonstrated for other flavonoids used in the therapy of
venostatic diseases [6].
Flavonoids inhibit in vitro human leukemic cell growth and,
in particular, ipriflavone reduces the in vitro clonogenic capacity
of patients' leukemic progenitors [4] with a slight reduction of
clonogenic capacity by normal bone marrow progenitors.
The mechanism of the antiproliferative activity of flavonoids remains to be fully clarified. Since flavonoids interact
with a variety of enzymes it is possible that their antiproliferative activity is mediated by these interactions [7, 8].
In view of the positive results obtained with ipriflavone and
the fact that quercetin appears to be more effective in inhibiting
CFU-L of sensitive cases in vitro [2, 3, 5], it appears worthwhile
to consider quercetin and its chemical derivatives as potential
therapeutic agents in the management of leukemia patients.
L. Pagano,1 L. Teofili,1 L. Mele,1 M. Piantelli,2
F. O. Ranelletti,3 F. Equitani,1 L. M. Larocca2 &
G. Leone1
l
Istituto di Semeiotica Medica,
logica, ^Cattedra di Istologia,
S. Cuore, Rome, Italy
2
Istituto Anatomia PatoUniversitd Cattolica del
Telomerase or telomersyn?
An article on telomerase at a meeting of our journal club was
recently the main focus of discussion. Why telomerase? Does
this enzyme bring death or life to the substance telomere?
We know that telomerase is the enzyme that synthesizes
telomeric DNA, leading to telomere extension [1]. What does
this suffix '-ase' actually mean? According to one dictionary, it
is used in naming enzymes and sometimes added to a part or
the whole of the name of the compound which the enzyme
decomposes [2], while according to another the suffix '-ase'
indicates an enzyme - moreover, a destructive substance [3].
When we look at the classification of enzymes [4] we see, in
general, that when this suffix comes at the end of a substrate's
name, it indicates that the word has a catabolic character, e.g.,
lipase, urease, amylase, protease, nucleotidase, nucleosidase,
ATP-ase, DNase, RNase; whereas when it comes at the end
of a word which defines reactions such as oxidation, dehydrogenation, hydroxylation, transfer, transamination, polymerization, or phosphorylation, the word - the enzyme - declares its
active involvement in such reaction.
After all, the suffix '-ase' at the end of the name of a
substrate such as telomere seems to imply a catabolic effect on
the ribonucleoprotein, the only known mechanism that can
stabilize telomere length in vertebrate organisms [5, 6]. In conclusion, for a better understanding of terminology, why not
'telomersyn' as an abbreviation of telomere synthetase?
I. H. Giillii & S. Marangoz
References
1. Markaverich BM, Roberts RR, Alejan'dro MA et al. Bioflavonoid
interaction with rat uterine type II binding sites and cell growth
inhibition. J Steroid Biochem 1988; 30: 71.
2. Hoffman R, Graham L, Newlands ES. Enhanced anti-proliferative
action of busulphan by quercetin on the human leukemia cell line
K.562. Br J Cancer 1989; 59: 347.
3. Larocca LM, Piantelli M, Leone G et al.Type II oestrogen binding
sites in acute lymphoid and myeloid leukaemias: Growth inhibitory
effect of oestrogen and flavonoids. Br J Haematol 1990; 75: 489.
4. Larocca LM, Teofili L, Leone G et al. Antiproliferative activity of
quercetin on normal bone marrow and leukemic progenitors. Br J
Haematol 1991; 79: 562.
5. Larocca LM, Teofili L, Sica S et al. Coercitin inhibits the growt of
leukemic progenitors and induces the expression of trasforming
growt-factor-BI in this cells. Blood 1995; 86: 3654-61.
6. Gugler R, Lschik M, Dengler MJ. Disposition of quercitin in man
after single oral and intravenous doses. Eur J Clin Pharmacol 1975;
229.
7. Kuriki Y, Racker E. Inhibition of (Na + , K.+) adenosine triphosphatase and its partial reactions by quercetin. Biochem 1976; 15: 4951.
8. Nishino H, Nagao M, Fujiki H, Sugimura T. Role of flavonoids in
suppressing the enhancement of phospholipid metabolism by tumor promoters Cancer Lett 1983; 21: 1.
Institute of Oncology, Hacettepe University, Ankara,
Turkey
References
1. Oliff A, Friend SH. Molecular targets for drug development. In
DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles
and Practice of Oncology. Philadelphia: Lippincott-Raven 1997;
3115-25.
2. Marckwardt AH, Cassidy FG, Hayakawa SI, McMillan JB. Funk
& Wagnalls Standard Dictionary. New York: Funk & Wagnalls 1970.
3. Gove PB. Webster's Third New International Dictionary. Massachusetts: G & C Merriam Company 1981.
4. Cayne BS. The Encyclopedia Americana. New York: Americana
Corporation 1974.
5. Morin GB. The human telomere terminal transferase enzyme is a
ribonucleoprotein that synthesizes TTAGGG repeats. Cell 1989;
59: 521-9.
6. Counter CM, Botelho FM, Wanf P et al. Stabilization of short
telomeres and telomerase activity accompany immortalization of
Epstein-Barr virus-transformed B lymphocytes. J Virol 1994; 68:
3410-4.