1. Biochem Pharmacol. 2004 Sep 15;68(6):981-8.
Phosphodiesterase inhibitors as anti-cancer drugs.
Hirsh L(1), Dantes A, Suh BS, Yoshida Y, Hosokawa K, Tajima K, Kotsuji F,
Merimsky O, Amsterdam A.
(1)Department of Molecular Cell Biology, The Weizmann Institute of Science,
Rehovot 76100, Israel.
It is well known that high intracellular levels of cAMP can effectively kill
cancer cells in vitro. Unfortunately substances elevating cAMP such as forskolin,
8-bromo-cAMP, 8-chloro-cAMP, monobutiryl or dibutiryl cAMP are not recommended to
be used as anti-cancer drugs because of their high cytotoxicity. In contrast
blockers of phosphodieterases such as theophylline and aminophylline, which could
elevate intracellular cAMP, are commonly used as anti-asthma drugs reaching
concentrations in the blood of 10-20 microg/ml. We tested the effectiveness of
theophylline and aminophylline to induce cell death alone or in combination with
common anti-cancer drugs such as cisplatin and gemcitabine (gemzar). We examined
such drug combinations in the induction of cell death in a variety of carcinoma
cell lines derived from human ovarian, prostate and lung cancer and in granulosa
cell line transformed by SV40 and Ras oncogene. While theophylline could induce
moderate cell death alone, at 20-25 microg/ml concentrations, aminophylline was
ineffective at this concentration. Theophylline (at 15-25 ng/ml) was found in all
four representative cell lines to synergize with gemcitabine or cisplatin to
induce programmed cell death, which permits a reduction in the effective doses of
cisplatin and gemcitabine by 2-3-fold. The effect of theophylline in induction of
apoptosis involved reduction of intracellular levels of Bcl2. Such a reduction
was proportional to the extent of apoptosis induced by theophylline as well as by
the combined drug treatments. Therefore, we propose that theophylline should be
considered as a potential anti-cancer drug in combination with other
chemotherapeutic drugs. Screening of other phosphodiesterase blockers, which are
not severely toxic, could open a possibility to improved chemotherapeutic cancer
treatments with reduced undesired side-effects. A clinical trial, using
theophylline as an anti-cancer drug, is currently being conducted in lung cancer
PMID: 15313391 [PubMed - indexed for MEDLINE]
2. Radiother Oncol. 2003 Sep;68(3):289-94.
Comparison between two iodine-125 brachytherapy implant techniques: pre-planning
and intra-operative by various dosimetry quality indicators.
Matzkin H(1), Kaver I, Bramante-Schreiber L, Agai R, Merimsky O, Inbar M.
(1)Department of Urology, Sourasky Tel Aviv Medical Center, Tel Aviv University,
6 Weizmann Street, Tel Aviv 64329, Israel.
PURPOSE: To prospectively compare two widely used seed implant techniques:
pre-planning and intra-operative planning, based on 1 month post-implant CT-based
METHODS: We report results of a detailed 1 month post-operative dosimetric
evaluation and comparison between 142 consecutive men with prostate
adenocarcinoma treated by the pre-planning methodology and 214 men treated with
the real-time, intra-operative seed implant method.
RESULTS: Baseline parameters patient's age, Gleason score, clinical stage, and
gland volume were similar in both groups (p>0.05). Length of physicist time and
operating room team time were more than double in the pre-planned group compared
to the intra-operative one (205 vs 100 min). Based on day 30 post-implant CT, for
patients treated with the pre-planning method, mean V90, V100 and V150 (percent
prostate volume receiving 90, 100 and 150% of the prescribed dose) were 67.5,
58.35 and 21.5%, respectively, while for the intra-operative group they were
97.9, 95.2 and 45%, respectively (p<0.01). Mean D90, expressed as percent of
target matched peripheral dose (minimal dose covering 90% of the gland volume)
was 53% for the pre-planned group and 114% for the intra-operative group of men
(p<0.01). Short-term morbidity was minimal in both groups and did not correlate
with the technique employed.
CONCLUSIONS: This large-scale comparison of implant adequacy favours real-time
intra-operative method. While all dosimetric parameters are significantly better
with this method, no increased early morbidity was noted. Longer-term PSA-based
clinical outcome should substantiate our contention of the superiority of the
intra-operative method when compared to the pre-planning one.
PMID: 13129637 [PubMed - indexed for MEDLINE]
3. Harefuah. 2001 Aug;140(8):694-8, 807.
[I125 prostate brachytherapy--short-term results of the first 150 patients in
[Article in Hebrew]
Matzkin H(1), Kaver I, Stenger A, Agai R, Esna N, Merimsky O.
(1)Departments of Urology and Oncology, E. Sourasky Tel Aviv Medical Center.
Prostate cancer is the most common malignancy among adult men. The treatment of
locally confined prostate cancer is either surgical or radiation therapy. In the
last decade or so a renewed method has gained popularity among patients and
physicians, the use of implantable I125 seeds into the prostate--named
brachytherapy.METHOD: We describe our first 150 cases treated with I125
brachytherapy with a follow-up after 3-24 months, median of 15 months. Twenty
patients had a combination of external beam radiation and brachytherapy.
RESULTS: Nadir PSA values of < 0.5 ng/ml were noted in 89%. This is accepted as
evidence of cure. In 6 men elevation of PSA was noted and interpreted as a
recurrence of disease. Associated morbidity was mild to moderate focusing on
lower urinary tract symptoms, for about 3 months. IPSS values, measuring urinary
symptoms after 3 months, resembled baseline levels. Impotence developed in 1/3 of
men as a result of treatment. This was assessed using a self-completed IIEF
questionnaire. No major complications (WHO grade III-IV) were noted in either
urinary system or lower gastro-intestinal tract.
IN CONCLUSION: We describe initial experience with Brachytherapy for the
treatment of prostate cancer in Israel. Our results compare favourably with those
published in American literature and profess moderate impact on quality of life
as well as transient effects on lower urinary tract symptoms, and a minimal
impotence rate (1/3) developing as a result of treatment. These results compare
favourably with morbidity rates cited for radical surgery or external beam
PMID: 11547468 [PubMed - indexed for MEDLINE]
4. Urology. 1989 Jan;33(1):59-60.
Late appearance of perineal implantation of prostatic carcinoma after perineal
Greenstein A(1), Merimsky E, Baratz M, Braf Z.
(1)Department of Urology, Ichilov Hospital, Sackler School of Medicine, Tel Aviv
A case is reported of a patient with carcinoma of the prostate and perineal tumor
implant five years after perineal needle biopsy. This is the second case of the
rare complication in which the implant appeared years after the biopsy. He was
treated with wide excision of the tumor.
PMID: 2911929 [PubMed - indexed for MEDLINE]
5. J Urol (Paris). 1986;92(9):617-9.
Spontaneous breakage of a double pigtail stent and bladder stone formation.
Papo J, Waizbard E, Merimsky E.
Five years after prostate resection and hormonal treatment for carcinoma of
prostate a 76 year old patient presented with bone and lung metastases and
dilatation of left upper collecting system. After castration a double J stent was
inserted in the ureter. Two years later he was admitted for alteration in general
condition related to cholecystitis. A standard radiograph showed the catheter
fractured into four pieces, although no urinary signs had been reported during
this 2-year period. Cholecystectomy was performed and the patient reviewed 6
weeks later: urography showed good functioning of the kidney and the absence of
obstruction of the collecting system. The process of fragmentation continued and
a bladder calculus developed on fragments falling into bladder: it was extracted
by lithotripsy. The patient was asymptomatic and refused further investigation or
treatment. This case is one of several reported in the literature and silicone or
C-flex should be substituted for polyethylene.
PMID: 3819464 [PubMed - indexed for MEDLINE]