Indications for Imatinib Mesylate Therapy and Clinical Management
Imatinib, the first clinically viable Abl kinase inhibitor, is the result of a medicinal chemistry project Analysis of structure activity relationships showed that. imatinib mesylate (Glivec), which was derived from a natural product by Novartis. . relationships (SAR) for cisplatin-type complexes, summarized by Cleare and. Imatinib is a small molecule kinase inhibitor used to treat certain types of cancer. of adverse effects can be increased when Cisplatin is combined with Imatinib. inducers, inhibitors and structure-activity relationships of human Cytochrome .
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- Indications for Imatinib Mesylate Therapy and Clinical Management
Cisplatin and oxaliplatin are clinically approved anticancer drugs. However, these drug conjugates were not intended for use in cancer chemotherapy. The salient properties of these conjugates are their stability in vivo and the feasibility for sustained drug release within the target cells.
In this paper, we report on the circumvention of TKI resistance, mediated by the secondary mutation of the oncogenic kinases, by the Pt-TKI hybrids in vitro. The hybrids were found to maintain specificity towards the same oncogenic kinase as the original TKI.
However, they were shown to bind to a slightly different site s in the ATP binding pocket of the kinases, thus allowing them to be less affected by the secondary mutation. Moreover, the observed dual mechanisms of action exhibited by the hybrid compounds, which include kinase inhibition and monofunctional DNA platination, may also explain the partial relief of drug resistance. Furthermore, most TKIs are substrates of multidrug resistance MDR transporters, which effectively pump the drugs out of cancer cells.
Since Pt drugs are not substrates of MDR transporters, we also intend to exploit the hybrid drug design approach to turn the TKI into non-substrate so as to avoid the transporters-mediated drug resistance and other related pharmacokinetic problems.
Results Chemistry The synthesis of the hybrid compounds 1a—1c, 2a—2c, 3a—3c is described in Fig. Three TKIs imatinib, erlotinib, vandetanib were individually conjugated to Pt-based anticancer agents cisplatin, oxaliplatin and transplatinrespectively, according to a published method with minor modifications Briefly, the Pt compounds were allowed to react with AgNO3 in equal molar ratio in dimethylformamide for 8 h at room temperature to facilitate the replacement of one Cl with a NO3 group.
The Pt nitrate product was obtained after filtration.
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Solvents were evaporated under reduced pressure. The crude hybrid compounds were further purified by size-exclusion Sephadex LH, GE Healthcare or silica gel C column chromatography using dimethylformamide or 0. If severe fluid retention occurs, imatinib should be discontinued and edema should be controlled with diuretics. Then, an attempt should be made to reinstitute imatinib treatment, possibly through dose escalation, while maintaining diuretic therapy at the required level [ 31 ].
The majority of imatinib-related cutaneous reactions consist of generalized rashes that are self-limiting in most cases and can be managed successfully with symptomatic support while imatinib therapy is continued [ 31 ]. Patients responding to treatment with imatinib should continue therapy if at all possible for as long as their disease response continues, as such patients usually lack alternatives for treatment of their cancers.
Specific causes of imatinib-related cutaneous reactions have not been identified. Because of its relatively low molecular weight, imatinib is unlikely to be immunogenic [ 39 ]. The dose dependency of adverse events supports the hypothesis that imatinib-related cutaneous reactions are mediated by changes in tyrosine kinase signaling rather than immunologic mechanisms [ 4041 ]. Mast cells and epidermal melanocytes express c-Kit [ 42 ].
While stimulation, rather than inhibition, of c-Kit has been proposed as a causative mechanism in atopic dermatitis [ 42 ], the possibility that altered c-Kit affects the development of epidermal inflammation and other changes in epidermal homeostasis merits further investigation.
Review of Cisplatin and Oxaliplatin in Current Immunogenic and Monoclonal Antibody Treatments
There is a report of localized depigmentation in a CML patient after 6 months of treatment with imatinib, possibly related to inhibition of the melanocyte c-Kit receptor tyrosine kinase [ 43 ]; vitiligo has also been reported. Interestingly, progressive repigmentation of the hair during imatinib treatment has also been observed [ 44 ].
These pigmentation changes required no intervention. Data from the major phase I and phase II studies suggest that the incidences and severities of cutaneous reactions to imatinib were dose dependent. A small study of cutaneous reactions in imatinib-treated patients confirmed the relationship between dosage on the one hand and rash and edema on the other, with female sex also being an independent risk factor [ 45 ].
The most common rash in patients receiving imatinib is characterized by macropapular lesions appearing most prominently on the forearms, trunk, and, occasionally, the face; pruritus is frequent [ 32 ].
Severe grade 3 or 4 exfoliative rashes have been reported in 0. Across all studies, involving 12, patients treated with imatinib for CML, the incidence of severe exfoliative rashes was approximately 1: There are a few reports of single cases of dermatologic reactions in imatinib-treated patients.
Three cases of acute generalized exanthematous pustulosis have been reported, as well as two cases of Stevens-Johnson syndrome, both in patients receiving imatinib for treatment of blast-crisis CML [ 4046 — 48 ]. One case each of pityriasis rosea and oral lichenoid reaction, possibly related to imatinib treatment, have also been described [ 4950 ].
The cutaneous reactions in these cases resolved after withdrawal of imatinib and institution of appropriate therapy for the dermatologic condition. Although imatinib was postulated to be the likely cause, confounding factors such as concomitant medications e. Interestingly, improvement in pre-existing dermatologic disease has also been observed: For drug-related cutaneous eruptions in general, early recognition of symptoms, withdrawal of the causative agent, and prompt initiation of symptomatic treatment are the mainstays of therapy [ 5253 ].Morphine Structure Activity Relationship
Vigilance is particularly warranted in the initial weeks of imatinib treatment. However, if equally effective alternative drugs are not available, it may be necessary to continue a course of treatment despite the presence of a cutaneous reaction [ 39 ].
Symptomatic management with antihistamines, salves, and coal tar preparations has proven useful in patients with mild-to-moderate imatinib-associated rashes. Topical or short-course oral glucocorticoid treatment can be used in patients unresponsive to more conservative measures [ 31 ].
Gradual dose escalation has made it possible to reinstitute imatinib therapy after the resolution of even severe desquamative rashes [ 3154 ]. Adverse skin effects in imatinib-treated patients have been successfully managed across the spectrum of severity.
As with other frequently occurring side effects, muscle pain is usually mild to moderate and manageable without reduction of the imatinib dose.
Muscle cramps in imatinib-treated patients usually occur in the hands, feet, calves, and thighs, and some patients may describe them in terms reminiscent of tetanic contractions. The cramps tend not to change over time with respect to pattern, frequency, and severity.
They do tend to have consistent triggers, and patients report experiencing them mainly at night or with exertion.