New vinca alkaloids in cancer treatment

teaser

Cindy Simoens
MSc
Research Assistant

Bea Pauwels

Filip Lardon

Jan B Vermorken
Laboratory of Cancer Research and Clinical Oncology
Department of Medical Oncology
University of Antwerp (UA/UZA)
Wilrijk (Antwerp)
Belgium
E:[email protected]

The clinical interest of vinca alkaloids was clearly identified as early as 1965. This class of compounds has been used as anticancer agents in the treatment of both haematological malignancies and several solid tumours for more than 40 years. Today, two natural compounds, vincristine and vinblastine, and two semisynthetic derivatives, vindesine and vinorelbine, have been registered and, thus, vinca alkaloids can be considered as representing a chemical class of definite utility in cancer chemotherapy.(1)

Mechanism of action
The antineoplastic properties of vinca alkaloids arise from their interaction with tubulin, the major component of microtubules in mitotic spindles. They diminish microtubule dynamics and assembly, resulting in the arrest of cell division at metaphase.

The order of overall affinity for tubulin is vincristine>vinblastine>vinorelbine>vinflunine.(2,3) This relative drug affinity for tubulin may be linked to the clinical doses used;(4) generally, vincristine is administered at 2mg/m(2) and vinflunine at 320mg/m(2).(5,6) However, ­clinical doses are also based on dose-limiting side-effects. Lobert et al hypothesised that the overall drug affinity for ­tubulin also contributes to the severity of the ­neuropathies observed clinically and therefore suggested that vinflunine is likely to result in reduced clinical neurotoxicity compared with other vinca alkaloids.(5)

Lobert et al also showed that the various vinca ­alkaloids have significantly different effects on tubulin spiral formation, and they proposed that the ability to make spirals is a direct measure of their ability to inhibit microtubule assembly and to promote microtubule disassembly, since it is the coupled formation of tubulin spirals that draws the drug into the cell. Vincristine, which makes the largest spirals, exhibits the longest relaxation times, while vinflunine, which makes the smallest spirals, exhibits the fastest relaxation times, thus correlating the size of the spirals induced with the half-life of drug retention. In these studies, it was also demonstrated that dosage and toxicity both correlate with the magnitude of the spiral size induced, with weaker drugs, such as ­vinflunine, potentially allowing for a wider margin between effective and toxic doses or an improved therapeutic index.(4, 5)

Clinical application of vincristine and vinblastine
Vincristine is an essential part of combination chemotherapy regimens for acute lymphocytic leukaemia and plays an important role in treatment of both Hodgkin and non-Hodgkin lymphomas. Vincristine has also been included in combinations used to treat a number of paediatric solid tumours and multiple myeloma, breast and small-cell lung cancer in adults. Vinblastine has been a key component of curative chemotherapy regimens for germ cell cancers of the testes, bladder cancer and advanced Hodgkin disease and in the past was frequently used in combinations to treat carcinoma of the breast and Kaposi’s sarcoma.(7)

Both drugs have valuable antitumour efficacy in the clinic, but there are considerable toxic side-effects associated with treatment with vincristine (neurotoxicity) and vinblastine (myelosuppresion).(7) Therefore, much effort has been devoted to identifying novel synthetic analogues that have a wider range of activity and are associated with less toxicity, resulting in a broader spectrum of anticancer efficacy.(8)

Clinical achievements of vinorelbine and vinflunine

IV vinorelbine as a single agent
Preclinical studies confirmed the antimitotic and cytotoxic activities of vinorelbine (see Figure 1), and it has since undergone extensive clinical development by Pierre Fabre Laboratories. To date, vinorelbine (Navelbine(®)) has been launched in more than 80 countries worldwide.(7)

[[HPE29_fig1_54]]

The activity of vinorelbine in the first-line treatment of advanced breast cancer (ABC) has been confirmed in many trials,(9) and the same is true for its activity in advanced nonsmall-cell lung cancer (NSCLC).(10) However, the main role of single-agent vinorelbine therapy is now in the first-line treatment of elderly patients suffering from disseminated breast cancer and NSCLC(9,11,12) or as second- or third-line salvage therapy after the failure of anthracyclines and/or taxanes in ABC.(9,13) Besides breast cancer and NSCLC, vinorelbine has defined promising levels of activity in a number of other malignancies, such as carcinomas of the prostate, oesophagus, uterine cervix, ovary and head and neck, multiple myeloma, small-cell lung cancer, mesothelioma and lymphomas.(9)

IV vinorelbine in  two- and three-drug combinations
One of the virtues of vinorelbine is the fact that, in view of its mild toxicity profile, it can be easily combined with virtually any other cytotoxic agent. A large number of phase II trials have been performed in this respect, which have generally shown encouraging activity, with an acceptable safety profile. Examples include combinations of vinorelbine with paclitaxel, docetaxel, ­doxorubicin, epirubicin, mitoxantrone, pegylated liposomal doxorubicin, mitomycin-C, gemcitabine, 5-fluoro uracil, platinum compounds, ifosfamide, irinotecan, estramustine and capecitabine.(9,14–23) Several triplets have also been investigated, but increased, sometimes unacceptable, toxicity was observed.(9,24–27) Some of these combinations were eventually investigated in phase III trials.(9,28,29) Recently, the interest in vinorelbine increased again as a result of the development and impressive success of the monoclonal antibody trastuzumab for patients with Her-2-overexpressing ABC. In a number of phase II clinical trials, the combination of ­trastuzumab and vinorelbine resulted in exquisite activity and excellent tolerability.(9)

IV vinorelbine in combination with radiation
In-vitro studies have shown that vinorelbine can ­potentiate the antitumour effects of radiation therapy,(30) which was confirmed in our laboratory (Simoens et al, in preparation). In a phase I study, Gridelli et al explored the feasibility of the combination of thoracic radiotherapy and concurrent daily administrations of vinorelbine as a radiosensitiser.(31) Moreover, vinorelbine has been included in several studies of sequential(32–37) or concurrent(33,35,38–46) chemoradiotherapy or as induction chemotherapy followed by concurrent chemo­radiation(47–50) with encouraging activity and an acceptable toxicity profile in various solid tumour types. Table 1 summarises the phase II studies of combined chemoradiotherapy with vinorelbine.

[[HPE29_table1_55]]

Oral vinorelbine
Owing to venous irritation at the injection site of vinorelbine and the convenience of oral therapy, an oral preparation of vinorelbine is under investigation. Given the severe toxicities that are observed during the first three weeks of administration, a new schedule has been developed, in which patients receive 60mg/m(2)/week in the first three weeks, which is then increased to 80mg/m(2)/week if no ­toxicity is observed.(9,51) Of interest, the dose-equivalents of oral:IV vinorelbine seem to be 80mg/m2:30mg/m(2) and 60mg/m2:25mg/m(2).(9,51) In ABC, these two formulations do not seem to differ in terms of efficacy or safety. In NSCLC, oral and IV vinorelbine have also been shown to have comparable activity.(9,51) An oral formulation of vinorelbine has been studied in a small trial involving hormone-refractory prostate cancer (HRPC) patients of 70 years of age and older. The preliminary data support that oral vinorelbine is a safe and moderately active option in the palliation of elderly HRPC patients.(52) Recently, an oral formulation of vinorelbine was also tested in elderly patients with NSCLC. It showed acceptable toxicity and an overall survival comparable to that observed with the IV formulation.(10) Contrary to these data, another phase II trial in elderly patients with metastatic breast cancer did not show activity of oral vinorelbine.(9) In paediatric cancer patients, a phase I evaluation of oral vinorelbine, administered weekly as a liquid-filled gelatin capsule at three times the IV dose, showed a relatively low (29%) and highly variable bioavailability. The dose-limiting toxicity was myelosuppression. The results of this trial precluded further development of this dose schedule of the oral formulation.(53)

Vinflunine in the clinic
Vinflunine (see Figure 2) was selected for clinical development on account of its markedly superior antitumour efficacy in preclinical in-vivo studies, compared with other vinca alkaloids.(54,55)

[[HPE29_fig2_54]]

Single-agent vinflunine was studied in several phase I trials utilising different treatment schedules,(6,56,59) ­leading to the selection of the three-weekly schedule with a recommended dose of 320mg/m(2) for phase II evaluation. Bennouna et al, using this three-weekly schedule in a phase I study, showed three partial responses (two in breast carcinoma, one in renal cell carcinoma) in heavily pretreated patients, which gave hope for a higher ­activity in less heavily pretreated patient populations.(6)

A phase II trial of vinflunine using the 320mg/m(2) dose level as second-line treatment in metastatic breast cancer after anthracycline/taxane failure reports a partial response in 35.6% and stable disease in 33.3% of evaluable patients.(57) Similarly encouraging results were seen in patients with NSCLC and advanced transitional cell carcinoma of the bladder who had failed first-line ­platinum-based regimens.(58,59) The toxicities seen in all three studies were similar to the phase I study, with neutropenia and constipation (manageable and noncumulative) prevailing. No grade 3 or more severe related peripheral neuropathy was seen.(57–59) Vinflunine as a single agent showed little benefit in metastatic renal cell carcinoma. However, it may be suggested that a combination with immunotherapy, angiogenesis inhibitors, gemcitabine, 5-FU or capecitabine may represent an avenue to explore in future studies of refractory renal cell carcinoma patients.(60)

The encouraging results from most of the phase II studies with vinflunine in refractory disease warrant further investigation in phase III trials in a number of tumour types, as second- or first-line treatment, either as a single agent or in combination with other active drugs.(58,59) At present, phase III trials are ongoing in NSCLC and bladder cancer. Other planned phase III programmes include studies in advanced breast cancer and ovarian cancer.(61) Vinflunine also appears to be a promising candidate for combining with other ­anticancer agents. Synergistic cytotoxicity was revealed when vinflunine was combined with cisplatin, mitomycin C,doxorubicin or 5-fluorouracil in vitro.(62)

Conclusion
Vinca alkaloids remain a drug family with a continuing interest for future anticancer therapy. New semisynthetic vinca alkaloids, developed to improve the therapeutic index of this class of drugs, are now being clinically evaluated. In that respect, both vinorelbine, a second-­generation vinca alkaloid, and vinflunine, a third-generation compound, showed promising results. Vinorelbine has a generally favourable safety profile and may be suitable for use in special populations such as the elderly and/or frail patient.(9) Vinflunine is also very promising because it causes even less ­neurotoxicity than vinorelbine and it has a superior (preclinical) antitumour activity relative to the other vinca alkaloids. This makes vinflunine an interesting addition to the currently available chemotherapeutic agents, and, hopefully, alone or in combination with other drugs, one that will lead to an improved spectrum of clinical activity.

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Resources
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Gridelli C, Aapro M, Ardizzoni A, et al. Treatment of advanced non-small-cell lung cancer in the elderly: results of an ­international expert panel. J Clin Oncol 2005;23(13):3125-37.
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Hill BT. Vinflunine, a second generation novel vinca alkaloid with a distinctive pharmacological profile, now in ­clinical development and prospects for future mitotic blockers. Curr Pharm Design 2001;7:1199-212.
Plant-derived drugs
W:www.phytomedical.com/Plant/
Vinblastine.asp
W:www.phytomedical.com/Plant/
Vincristine.asp
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Vinorelbine.asp