5-Flourouracil
5-fluorouracil (5-FU) is an antimetabolite analogue of the pyrimidine
uracil, with a fluorine atom at the C-5 position in place of hydrogen79. Intracellularly, the fluoropyrimidine is converted
into fluorodeoxyuridine monophosphate (FdUMP), fluorodeoxyuridine
triphosphate (FdUTP) and fluorouridine triphosphate (FUTP) which become
mis-incorporated into RNA and DNA 80. Furthermore,
FdUMP inhibits the enzyme thymidylate synthase by competitively binding
to its active site thereby blocking binding of the normal substrate dUMP
and inhibiting dTMP synthesis 81,82. Because of its
cytotoxicity, 5-FU is used widely as a chemotherapeutic agent in cancer
treatment. Topical 5-FU cream is used for treatment of intraepithelial
neoplasia of the skin and off-license treatment of HPV related lesions
including genital warts, vulvar intraepithelial neoplasia and vaginal
intraepithelial neoplasia 83,84.
The safety profile of 5-FU was established in a randomized controlled
study involving 90 women with HPV-associated vaginal and vulval lesions.
Women who used prophylactic topical 5–FU at a dosage of 2 g once every
two weeks after ablative therapy, were significantly less likely to
develop recurrent lesions than controls 85. In a later
study where the drug was used for vaginal HPV-associated lesions
continuously over five to seven days, or periodically once a week for 10
weeks, dose and duration dependent chronic mucosal ulceration developed
in 8.2% of subjects 86. In a separate study, 5-FU was
used as an adjunctive treatment following excisional therapy for CIN 2-3
in HIV positive patients in order to prevent recurrence50. A dosage of 2 g of 5% 5-FU cream was
self-administered using vaginal applicators at bedtime once every two
weeks for six months. The recurrence rate in the treatment arm was 28%
compared to 47% in the observation arm and there was a statistically
significant prolonged time to recurrence in the treatment arm compared
to the observation group. Once again vaginal 5-FU at this dosage and
interval was extremely well tolerated, with minimal morbidity in
HIV-infected women with CIN 50.
Another trial investigated intravaginal 5% 5-FU vs standard-of-care
observation in young women aged 18 – 29 years with CIN 2 with the
primary outcome of disease regression at six months after the diagnosis
of CIN 2 51. Dual contraception with condoms plus one
either oral, intravaginal, injectable, implantable, or intrauterine
device was required for the 5-FU group because of its potential
teratogenic effects. The established dosage of 2 g of topical 5% 5-FU
cream was applied once every two weeks for a period of 16 weeks (a total
of eight doses) which is standard with other studies87–90. This was inserted into the vagina at night
using a vaginal applicator, and a tampon placed per vagina overnight to
keep the cream in-situ, and then removed in the morning. Disease
regression was demonstrated in 84% of women in the 5-FU group compared
to 52% of women in the observation group, and after six months and the
treated group was twice as likely to be both HPV negative and clear of
neoplasia 51.
As described above, one of the drawbacks of using a vaginal cream based
locoregional therapy is the inability to control the precise site of
application and the duration of drug action, resulting in local and
systematic side effects 91,92. In an effort to
circumvent this problem, 5‐FU was incorporated into a one-way release
bilaminar bio-adhesive drug delivery system 93 which
was placed directly on the cervix using a device applicator, and keptin situ for 24 hours, after which time it was removed using
threads that were attached to it for that purpose, releasing a once only
dose of 20 mg. This study involved 104 patients with CIN 1 and 2, where
the control arm received the delivery system loaded with a placebo. The
device was spontaneously expelled in four patients before the 24 hours
was up, and 41% of patients in the drug arm developed erythema of the
cervix compared to only 8% in the placebo group. More importantly,
there was no difference in remission of CIN between drug and placebo
groups 93. The authors concluded that despite the
effectiveness of the delivery system, one application of 5‐FU was not
effective in the treatment of CIN due to inadequate dosage.
In a separate bid to achieve better therapeutic efficacy and increased
patient compliance, 5-FU was formulated in a vaginal gel with
thermosensitive and muco-adhesive properties in order to increase
residence time at the cervix 94. The drug was
incorporated as its inclusion complex in a 1:1 molar ratio with either
b-cyclodextrin or hydroxypropyl-b-cyclodextrin in order to increase its
aqueous solubility and to achieve the complete release of 5-FU from the
gel and this did not affect the gelling temperature significantly94. The muco-adhesive polymer HPMC conferred favorable
thermosensitive in situ gelling properties and complexation to
cyclodextrins resulted in a ten-fold increase in cytotoxicity against
HeLa cells 94. This was also confirmed by the enhanced
release profile of 5-FU through complexation 94. All
this suggesting that formulating an anticancer drug in a muco-adhesive,
thermosensitive gel in complexation with cyclodextrins can increase its
anticancer activity resulting in lower doses and reduced unwanted side
effects through controlled release and prolonged residence time at the
administration site. The disadvantages of 5-FU are its potential for
teratogenic effects in its intravenous form in women of child-bearing
age and for causing cervical mucosal ulceration 86thereby potentially placing women at increased risk of sexually
transmitted infections 51.